Histone demethylase inhibitors

ABSTRACT

The present invention relates generally to compositions and methods for treating cancer and neoplastic diseases. Provided herein are substituted imidazole-pyridine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of histone demethylase enzymes. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as pancreatic cancer, prostate cancer, breast cancer, bladder cancer, lung cancer, gastric cancer, leukemia and/or melanoma and the like.

CROSS-REFERENCE

This application is a divisional of U.S. patent application Ser. No.14/855,269, filed Sep. 15, 2015, which claims the benefit of U.S.Provisional Application 62/051,268, filed Sep. 16, 2014, which isincorporated herein by reference in its entirety.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic diseases.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted imidazole-pyridine derivative compoundsand pharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful for the inhibition of histonedemethylases. Furthermore, the subject compounds and compositions areuseful for the treatment of cancer, such as pancreatic cancer, prostatecancer, breast cancer, bladder cancer, lung cancer, gastric cancer,leukemia and/or melanoma and the like. The substitutedimidazole-pyridine derivative compounds described herein are based upona substituted 2-(1H-imidazol-4-yl)pyridine ring system bearing a fusedor linked triazole ring system.

One embodiment provides a compound having the structure of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —NH₂, —NH(C₁-C₃alkyl) or C₁-C₃alkyl;-   R⁴ is hydrogen, C₁-C₄alkyl, C₁-C₄alkene, C₁-C₄alkyne, halogen, or    —CN; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

One embodiment provides a compound having the structure of Formula (II),

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is hydrogen, halogen, —OH, —OR⁴, —N(R⁴)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —NH₂, —NH(C₁-C₃alkyl) or C₁-C₃alkyl;    and-   each R⁴ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient. One embodiment provides apharmaceutical composition comprising a compound of Formula (II), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

One embodiment provides a method for inhibiting a histone demethylaseenzyme comprising contacting the histone demethylase enzyme with acompound of Formula (I). One embodiment provides a method for inhibitinga histone demethylase enzyme comprising contacting the histonedemethylase enzyme with a compound of Formula (II).

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(I), or a pharmaceutically acceptable salt thereof. One embodimentprovides a method of treating cancer in a patient in need thereof,comprising administering to the patient a compound of Formula (II), or apharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds.) A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedimidazole-pyridine derivative compounds described herein is intended toencompass any and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Substituted Imidazole-Pyridine Derivative Compounds

Substituted imidazole-pyridine derivative compounds are described hereinthat inhibit a histone demethylase enzyme. These compounds, andcompositions comprising these compounds, are useful for the treatment ofcancer and neoplastic diseases. The compounds described herein may,therefore, be useful for treating pancreatic cancer, prostate cancer,breast cancer, bladder cancer, lung cancer, gastric cancer, leukemiaand/or melanoma and the like.

One embodiment provides a compound having the structure of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —NH₂, —NH(C₁-C₃alkyl) or C₁-C₃alkyl;-   R⁴ is hydrogen, C₁-C₄alkyl, C₁-C₄alkene, C₁-C₄alkyne, halogen, or    —CN; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R³ is hydrogen.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is alkyl. Anotherembodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein R² is methyl.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is carbocyclyl orcarbocyclylalkyl. Another embodiment provides a compound of Formula (I),or a pharmaceutically acceptable salt thereof, wherein R² is—(C₁-C₆alkylene)carbocyclyl. Another embodiment provides a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein R²is —(C₁-C₆alkylene)carbocyclyl and the (C₁-C₆alkylene) is a C₁alkylene,or a C₂alkylene.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is—(C₁-C₆alkylene)carbocyclyl and the carbocyclyl is1,2,3,4-tetrahydronaphthyl optionally substituted with one or moregroups selected from halogen, hydroxy, —CN, alkyl, alkoxy, alkylamino,aryl, carbocyclyl, heterocyclyl, carbocyclylalkyl, andheterocyclylalkyl.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is heterocyclyl orheterocyclylalkyl.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is heteroaryl orheteroarylalkyl.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is aryl or aralkyl.Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is aralkyl, and thearalkyl is —(C₁-C₆alkylene)aryl. Another embodiment provides a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, whereinR² is aralkyl, the aralkyl is —(C₁-C₆alkylene)aryl and the(C₁-C₆alkylene) is C₁alkylene, or a C₂alkylene.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is aryl or aralkyl,and the aryl is a phenyl optionally substituted with one or more groupsselected from halogen, hydroxy, —CN, alkyl, alkoxy, alkylamino, aryl,carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R² is aryl or aralkyl,and the aryl is naphthyl optionally substituted with one or more groupsselected from halogen, hydroxy, —CN, alkyl, alkoxy, alkylamino, aryl,carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen,halogen, —CN, or an alkyl optionally substituted with at least onefluoro. Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R⁴ is fluoro. Anotherembodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is chloro. Another embodimentprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein R⁴ is iodo. Another embodiment provides a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, whereinR⁴ is —CN. Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R⁴ is —CF₃.

Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen oraryl. Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen.Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is aryl. Anotherembodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is aryl and the aryl is a phenyloptionally substituted with one or more groups selected from halogen,hydroxy, —CN, alkyl, alkoxy, —O— (cycloalkylalkyl), alkylamino, aryl,carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl.Another embodiment provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is aryl, and thearyl is a phenyl is substituted with one or more groups selected fromhalogen, alkoxy, or —O-(cycloalkylalkyl).

One embodiment provides a compound having the structure of Formula (Ia),

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is aryl, or heteroaryl; wherein R¹ is optionally substituted with    halogen, —OH, —CN, alkyl, carbocyclyl, heterocyclyl, aryl,    heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl,    heteroarylalkyl, alkyl-O—, carbocyclyl-O—, heterocyclyl-O—, aryl-O—,    heteroaryl-O—, carbocyclylalkyl-O—, heterocyclylalkyl-O—,    aralkyl-O—, or heteroarylalkyl-O—;-   R² is methyl;-   R³ is hydrogen; and-   R⁴ is hydrogen, C₁-C₄alkyl, C₁-C₄alkene, C₁-C₄alkyne, halogen, or    —CN.

Another embodiment provides the compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁴ is C₁-C₄alkyl.Another embodiment provides the compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R⁴ is C₁-C₄alkyl, andthe alkyl is substituted with at least one fluoro. Another embodimentprovides the compound of Formula (Ia), or a pharmaceutically acceptablesalt thereof, wherein R⁴ is CH₂F, CHF₂, or CF₃. Another embodimentprovides the compound of Formula (Ia), or a pharmaceutically acceptablesalt thereof, wherein R⁴ is CF₃.

Another embodiment provides the compound of Formula (Ia), or apharmaceutically acceptable salt thereof, wherein R¹ is aryl. Anotherembodiment provides the compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof, wherein R¹ is heteroaryl. Another embodimentprovides the compound of Formula (Ia), or a pharmaceutically acceptablesalt thereof, wherein R¹ is aryl, and the aryl is optionally substitutedwith halogen, alkyl-O—, carbocyclyl-O—, heterocyclyl-O—, aryl-O—,heteroaryl-O—, carbocyclylalkyl-O—, heterocyclylalkyl-O—, aralkyl-O—, orheteroarylalkyl-O—. Another embodiment provides the compound of Formula(Ia), or a pharmaceutically acceptable salt thereof, wherein R¹ is aryl,and the aryl is optionally substituted with halogen, alkyl-O—,carbocyclyl-O—, heterocyclyl-O—, aryl-O—, heteroaryl-O—,carbocyclylalkyl-O—, heterocyclylalkyl-O—, aralkyl-O—, orheteroarylalkyl-O—.

One embodiment provides a compound having the structure of Formula (Ib),

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is hydrogen;-   R² is chosen from —(C₁-C₆alkylene)-(1,2,3,4-tetrahydronaphthyl),    —(C₁-C₆alkylene)-(indanyl), —(C₁-C₆alkylene)-(chromanyl),    —(C₁-C₆alkylene)-(dihydrobenzofuranyl)-   R³ is hydrogen; and-   R⁴ is hydrogen, C₁-C₄alkyl, C₁-C₄alkene, C₁-C₄alkyne, halogen, or    —CN.

Another embodiment provides the compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R² is chosen from—(C₁-C₆alkylene)-(1,2,3,4-tetrahydronaphthyl), optionally substitutedwith one or more groups selected from halogen, hydroxy, —CN, alkyl,alkoxy, alkylamino, aryl, carbocyclyl, carbocyclyloxy, heterocyclyl,carbocyclylalkyl, carbocyclylalkyloxy, and heterocyclylalkyl.

Another embodiment provides the compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R² is chosen from—(C₁-C₆alkylene)-(indanyl), optionally substituted with one or moregroups selected from halogen, hydroxy, —CN, alkyl, alkoxy, alkylamino,aryl, carbocyclyl, carbocyclyloxy, heterocyclyl, carbocyclylalkyl,carbocyclylalkyloxy, and heterocyclylalkyl.

Another embodiment provides the compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R² is chosen from—(C₁-C₆alkylene)-(chromanyl), optionally substituted with one or moregroups selected from halogen, hydroxy, —CN, alkyl, alkoxy, alkylamino,aryl, carbocyclyl, carbocyclyloxy, heterocyclyl, carbocyclylalkyl,carbocyclylalkyloxy, and heterocyclylalkyl.

Another embodiment provides the compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R² is chosen from—(C₁-C₆alkylene)-(dihydrobenzofuranyl), optionally substituted with oneor more groups selected from halogen, hydroxy, —CN, alkyl, alkoxy,alkylamino, aryl, carbocyclyl, carbocyclyloxy, heterocyclyl,carbocyclylalkyl, carbocyclylalkyloxy, and heterocyclylalkyl.

Another embodiment provides the compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁴ is C₁-C₄alkyl.Another embodiment provides the compound of Formula (Ib), or apharmaceutically acceptable salt thereof, wherein R⁴ is C₁-C₄alkyl, andthe alkyl is substituted with at least one fluoro. Another embodimentprovides the compound of Formula (Ib), or a pharmaceutically acceptablesalt thereof, wherein R⁴ is CH₂F, CHF₂, or CF₃. Another embodimentprovides the compound of Formula (Ib), or a pharmaceutically acceptablesalt thereof, wherein R⁴ is CF₃.

One embodiment provides a compound having the structure of Formula (Ic),

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R³ is hydrogen;-   R⁴ is hydrogen, C₁-C₄alkyl, C₁-C₄alkene, C₁-C₄alkyne, halogen, or    —CN; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R² is alkyl. Anotherembodiment provides the compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R² is methyl.

Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R² is carbocyclyl orcarbocyclylalkyl. Another embodiment provides the compound of Formula(Ic), or a pharmaceutically acceptable salt thereof, wherein R² is—(C₁-C₆alkylene)carbocyclyl. Another embodiment provides the compound ofFormula (Ic), or a pharmaceutically acceptable salt thereof, whereincarbocyclyl is 1,2,3,4-tetrahydronaphthyl optionally substituted withone or more groups selected from halogen, hydroxy, —CN, alkyl, alkoxy,alkylamino, aryl, carbocyclyl, heterocyclyl, carbocyclylalkyl, andheterocyclylalkyl. Another embodiment provides the compound of Formula(Ic), or a pharmaceutically acceptable salt thereof, wherein the(C₁-C₆alkylene) is a C₁alkylene, or a C₂alkylene. Another embodimentprovides the compound of Formula (Ic), or a pharmaceutically acceptablesalt thereof, wherein R² is heterocyclyl or heterocyclylalkyl. Anotherembodiment provides the compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R² is heteroaryl or heteroarylalkyl.Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R² is aryl or aralkyl.Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein the aralkyl is—(C₁-C₆alkylene)aryl.

Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein the aryl is a phenyloptionally substituted with one or more groups selected from halogen,hydroxy, —CN, alkyl, alkoxy, alkylamino, aryl, carbocyclyl,heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl. Anotherembodiment provides the compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein (C₁-C₆alkylene) is C₁alkylene, or aC₂alkylene. Another embodiment provides the compound of Formula (Ic), ora pharmaceutically acceptable salt thereof, wherein aryl is naphthyloptionally substituted with one or more groups selected from halogen,hydroxy, —CN, alkyl, alkoxy, alkylamino, aryl, carbocyclyl,heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl. Anotherembodiment provides the compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein (C₁-C₆alkylene) is C₁alkylene, or aC₂alkylene.

Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen oraryl. Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen.Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R¹ is aryl. Anotherembodiment provides the compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein the aryl is a phenyl optionallysubstituted with one or more groups selected from halogen, hydroxy, —CN,alkyl, alkoxy, —O-(cycloalkylalkyl), alkylamino, aryl, carbocyclyl,heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl. Anotherembodiment provides the compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein the phenyl is substituted with one ormore groups selected from halogen, alkoxy, or —O-(cycloalkylalkyl).

Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁴ is —CN. Anotherembodiment provides the compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₁-C₄alkene, or C₁-C₄alkyne.Another embodiment provides the compound of Formula (Ic), or apharmaceutically acceptable salt thereof, wherein R⁴ is halogen. Anotherembodiment provides the compound of Formula (Ic), or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₁-C₄alkyl. Another embodimentprovides the compound of Formula (Ic), or a pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁-C₄alkyl, and the alkyl is substitutedwith at least one fluoro. Another embodiment provides the compound ofFormula (Ic), or a pharmaceutically acceptable salt thereof, wherein R⁴is CH₂F, CHF₂, or CF₃. Another embodiment provides the compound ofFormula (Ic), or a pharmaceutically acceptable salt thereof, wherein R⁴is CF₃.

One embodiment provides a compound having the structure of Formula (II),

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is hydrogen, halogen, —OH, —OR⁴, —N(R⁴)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —NH₂, —NH(C₁-C₃alkyl) or C₁-C₃alkyl;    and-   each R⁴ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R³ is hydrogen.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is alkyl. Anotherembodiment provides a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, wherein R² is methyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is carbocyclyl orcarbocyclylalkyl. Another embodiment provides a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R² is—(C₁-C₆alkylene)carbocyclyl. Another embodiment provides a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein R²is —(C₁-C₆alkylene)carbocyclyl, and the (C₁-C₆alkylene) is a C₁alkylene,or a C₂alkylene.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is—(C₁-C₆alkylene)carbocyclyl, and the carbocyclyl is1,2,3,4-tetrahydronaphthyl optionally substituted with one or moregroups selected from halogen, hydroxy, —CN, alkyl, alkoxy,—O-(cycloalkylalkyl), alkylamino, aryl, carbocyclyl, heterocyclyl,carbocyclylalkyl, and heterocyclylalkyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is heterocyclyl orheterocyclylalkyl. Another embodiment provides a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R² is—(C₁-C₆alkylene)heterocyclyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is heteroaryl orheteroarylalkyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is heteroaryl orheteroarylalkyl, and the heteroaryl is pyridine or pyrimidine optionallysubstituted with one or more groups selected from halogen, hydroxy, —CN,alkyl, alkoxy, —O-(cycloalkylalkyl), alkylamino, aryl, carbocyclyl,heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is heteroaryl, andthe heteroaryl is a chromanyl optionally substituted with one or moregroups selected from halogen, hydroxy, —CN, alkyl, alkoxy, —O—(cycloalkylalkyl), alkylamino, aryl, carbocyclyl, heterocyclyl,carbocyclylalkyl, and heterocyclylalkyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is heteroarylalkyl,and the heteroarylalkyl comprises a chromanyl optionally substitutedwith one or more groups selected from halogen, hydroxy, —CN, alkyl,alkoxy, —O-(cycloalkylalkyl), alkylamino, aryl, carbocyclyl,heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl; and a C₁alkylene,or a C₂alkylene.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is aryl or aralkyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is aryl or aralkyl,and the aryl is a phenyl optionally substituted with one or more groupsselected from halogen, hydroxy, —CN, alkyl, alkoxy, —O—(cycloalkylalkyl), alkylamino, aryl, carbocyclyl, heterocyclyl,carbocyclylalkyl, and heterocyclylalkyl. Another embodiment provides acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein R² is aryl or aralkyl, and the aryl is phenyl optionallysubstituted with one or more groups selected from halogen, alkoxy, andalkyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is aralkyl, and thearalkyl is a —(C₁-C₆alkylene)aryl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is aralkyl, thearalkyl is a —(C₁-C₆alkylene)aryl, and the aryl is a phenyl optionallysubstituted with one or more groups selected from halogen, hydroxy, —CN,alkyl, alkoxy, —O-(cycloalkylalkyl), alkylamino, aryl, carbocyclyl,heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is aralkyl, thearalkyl is a —(C₁-C₆alkylene)aryl, and the (C₁-C₆alkylene) is aC₁alkylene, or a C₂alkylene.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R² is aralkyl, and thearalkyl comprises a naphthyl optionally substituted with one or moregroups selected from halogen, hydroxy, —CN, alkyl, alkoxy, —O—(cycloalkylalkyl), alkylamino, aryl, carbocyclyl, heterocyclyl,carbocyclylalkyl, and heterocyclylalkyl. Another embodiment provides acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein the aralkyl further comprises a C₁alkylene, or a C₂alkylene.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen oraryl. Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is aryl.

Another embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is aryl, and thearyl is a phenyl optionally substituted with one or more groups selectedfrom halogen, hydroxy, —CN, alkyl, alkoxy, —O-(cycloalkylalkyl),alkylamino, aryl, carbocyclyl, heterocyclyl, carbocyclylalkyl, andheterocyclylalkyl. Another embodiment provides a compound of Formula(II), or a pharmaceutically acceptable salt thereof, wherein R¹ is aryl,and the aryl is a phenyl optionally substituted with one or more groupsselected from halogen, alkoxy, or —O-(cycloalkylalkyl).

In some embodiments, the compound disclosed herein has the structureprovided in Table 1.

TABLE 1 Chemical Synthesis Example Structure Name 1

2-(1-methylimidazol-4-yl)-4-(1H-triazol-4- yl)pyridine 2

2-[1-[(2-chlorophenyl)methyl]imidazol-4- yl]-4-(1H-triazol-4-yl)pyridine3

2-[5-(4-fluorophenyl)-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 4

2-[5-[2-(cyclopropylmethoxy)-4- fluorophenyl]-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 5

2-[1-(1-phenylethyl)imidazol-4-yl]-4-(1H- triazol-4-yl)pyridine 6

2-[1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 7

2-[1-[2-(2-methoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 8

2-[1-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)imidazol-4-yl]-4-(1H-triazol-4- yl)pyridine 9

2-[1-[2-(2-ethoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 10

4-(1H-triazol-4-yl)-2-[1-[2-[2-(2,2,2-trifluoroethoxy)phenyl]ethyl]imidazol-4- yl]pyridine 11

2-[1-[2-[2- (cyclopropylmethoxy)phenyl]ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 12

2-[1-(3,4-dihydro-2H-chromen-4- ylmethyl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 13

4-[2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile 14

4-[2-[1-[(2,3- dichlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile 15

4-[2-[1-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)imidazol-4-yl]pyridin-4-yl]-1H- triazole-5-carbonitrile 16

4-[2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile 17

2-[1-[2-(2- phenylmethoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 18

2-[1-[2-(2-phenoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 19

2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(5-iodo-1H-triazol-4-yl)pyridine 20

2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(5-fluoro-1H-triazol-4-yl)pyridine 21

2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 22

2-[1-[[2-chloro-3- (trifluoromethyl)phenyl[methyl[imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 23

2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]- 4-(1H-triazol-4-yl)pyridine24

2-[5-(4-fluoro-3-methoxyphenyl)-1- methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 25

2-[5-(3-ethoxy-4-fluorophenyl)-1- methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 26

2-[1-[[2-fluoro-3- (trifluoromethoxy)phenyl]methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 27

2-[1-[2-(2-phenylphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 28

2-[1-[(2-fluoro-3- methylphenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridin 29

2-[1-[(3-chloro-2- fluorophenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 30

2-[1-[(2-fluoro-3- methoxyphenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 31

4-(1H-triazol-4-yl)-2-[1-[2-[2-(trifluoromethyl)phenyl]ethyl]imidazol-4- yl]pyridine 32

2-[1-[2-(2-chlorophenyl)-2- methylpropyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 33

2-[1-(1-phenylpropan-2-yl)imidazo1-4-yl]-4- (1H-triazol-4-yl)pyridine 34

4-(1H-triazol-4-yl)-2-[1-[2-[2-(trifluoromethoxy)phenyl]ethyl]imidazol-4- yl]pyridine 35

4-(5-fluoro-1H-triazol-4-yl)-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine 36

4-(5-chloro-1H-triazol-4-yl)-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine 37

2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]-4-[5-(trifluoromethyl)-1H-triazol-4- yl]pyridine 38

4-(5-iodo-1H-triazol-4-yl)-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine 39

4-[2-[5-[2-(cyclopropylmethoxy)-4- fluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile 40

4-(5-chloro-1H-triazol-4-yl)-2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1- methylimidazol-4-yl]pyridine 41

2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-(5-fluoro-1H-triazol-4-yl)pyridine 42

1-(cyclopropylmethyl)-4-{1H- [1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole 43

4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1-(2,2,2-trifluoroethyl)-1H-imidazole 44

1-benzyl-4-{1H-[1,2,3]triazolo[4,5- c]pyridin-6-yl}-1H-imidazole 45

1-[(2-chlorophenyl)methyl]-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 46

1-[(3-chlorophenyl)methyl]-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl]-1H- imidazole 47

1-[(4-chlorophenyl)methyl]-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 48

1-[(3,4-dichlorophenyl)methyl]-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 49

1-(4-chlorophenyl)-4-{1H- [1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole 50

1-(2-chlorophenyl)-4-{1H- [1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole 51

1-(3-chlorophenyl)-4-{1H- [1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole 52

1-(3,5-dichlorophenyl)-4-{1H- [1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole 53

5-(4-fluorophenyl)-1-methyl-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 54

5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methyl-4-{1H-[1,2,3]triazolo[4,5- c]pyridin-6-yl}-1H-imidazole 55

2-(5-bromo-1-(2-chlorobenzyl)-1H- imidazol-4-yl)-4-(2H-1,2,3-triazol-4-yl)pyridine 56

2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(5-trifluoromethyl-1H-triazol-4- yl)pyridine

In some embodiments, the compound disclosed herein has the structureprovided in Table 2.

TABLE 2

Preparation of the Substituted Imidazole-Pyridine Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation, include for example, “SyntheticOrganic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler etal., “Organic Functional Group Preparations,” 2nd Ed., Academic Press,New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist,“Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.March, “Advanced Organic Chemistry: Reactions, Mechanisms andStructure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the substituted imidazole-pyridine derivativecompounds described herein is P. H. Stahl & C. G. Wermuth “Handbook ofPharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

The substituted 4-triazolylpyridine derivative compounds are prepared bythe general synthetic route described below in Scheme 1-4.

Referring to Scheme 1, 2-chloro-4-pyridinenitrile (1-0) undergoes Stillecoupling with tin reagent, N-methyl-4-(tributylstannyl)imidazole ortrityl protected tributyltin imidazole, in presence of a catalyst, suchas tetrakis(triphenylphosphine) palladium (0), under heating condition,i.e. 130° C., to give the coupling products 1-1 and 1-2. Deprotection ofthe trityl protective group is performed using acids, such as aceticacid and TFA, at room temperature to give compound 1-3, which is thenalkylated with halogenated alkyl derivative or mesylated derivative togive 1-4. Reaction of the nitrile intermediates 1-1 and 1-4 with TMSdiazomethane, in presence of n-butyllithium, in an anhydrous organicsolvent, such as THF, provides TMS protected 4-triazolopyridineintermediate 1-5, which undergoes deprotection using a base, such asNaOH, in an organic solvent, such as MeOH, under heating condition (i.e.50° C.) to give the final product, compound 1-6.

Synthesis of substituted 2-imidazole 4-triazolopyridine derivatives isdescribed in Scheme 2.2-(1-Methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile is brominated byusing stoichiometric amount of NBS in an organic solvent, such asmethylene chloride, to give brominated intermediate 2-1. Compound 2-1then undergoes Suzuki coupling with an aromatic boronic acid or ester togive 2-2. The nitrile group is then hydrolyzed to the acid (2-3) byrefluxing in a solvent mixture of concentrated NaOH (i.e. 5N or 6N) andEtOH. The acid is then reduced to the alcohol (2-4) by using LiAlH₄ inan organic solvent, such as THF. The primary alcohol is then treatedwith Dess-Martin oxidant to provide the aldehyde 2-5, which subsequentlyreacts with 2-(benzenesulfonyl)acetonitrile in presence of a base, suchas NaHCO₃, in an alcoholic solvent, such as EtOH, to give theintermediate 2-6, which then reacts with NaN₃ in DMF under heatingcondition, i.e. 100° C., to afford the 4-triazolopyridine compound 2-7.

Referring to Scheme 3, similar to Scheme 1, intermediate 1-4 can also besynthesized from 4-amide-2-imidazole pyridine (3-0). Alkylation usingeither halogenated RX or mesylate ROMs gives 3-1, which can be convertedto nitrile intermediate 1-4 using trifluoroacetic anhydride, in presenceof excess of pyridine (i.e. 3 equiv.) in an organic solvent, such asmethylene chloride. Final compounds 3-6 can then be obtained usingsimilar procedures as described in Scheme 2.

Synthesis of substituted triazole analogs 4-4 is shown in Scheme 4.Starting from the aldehyde 3-7, (1-diazo-2-oxo-propyl)-phosphonic aciddimethyl ester is added to a mixture of the aldehyde and a base, such aspotassium carbonate, in an alcoholic solvent, i.e. MeOH, to give thealkyne intermediate (4-1). It is then added to a mixture of PMBprotected azide and KI in THF, in presence of a copper complex and abase, such as triethylamine, to give the iodo-triazole intermediate 4-2.Conversion of the iodo to various substitutions can be accomplished bytreating 4-2 with KF, KCl or TMSCF₃ in a solvent mixture, such as CH₃CNand H₂O, and heated at elevated temp., i.e. 160° C., in a microwaveoven, followed by deprotection of the PMB group using TFA under heatingcondition, i.e. 60° C., to give the final compounds 4-4.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

The substituted azabenzotriazole derivative compounds are prepared bythe general synthetic route described below in Scheme 5.

Referring to Scheme 5, treatment of diaminopyridine 5-1 withdiazotization reagent afforded azabenzotriazole 5-2, which wassubsequently protected with a SEM protecting group. Carbonylation of 5-3in the presence of methanol and Palladium catalyst furnished 5-4 whichwas reduced to alcohol 5-5 and re-oxidized to corresponding aldehyde5-6. Treatment with Ts-MIC reagent followed by ammonia workup furnishedimidazole 5-7. Alkylation with alkylhalide under basic conditions orcoupling with a boronic acid under Chan-Lam reaction conditions afforded5-8. Removal of SEM protecting group under strongly acidic conditionsfurnished 5-9.

Pharmaceutical Compositions

In certain embodiments, the substituted imidazole-pyridine derivativecompound as described herein is administered as a pure chemical. Inother embodiments, the substituted imidazole-pyridine derivativecompound described herein is combined with a pharmaceutically suitableor acceptable carrier (also referred to herein as a pharmaceuticallysuitable (or acceptable) excipient, physiologically suitable (oracceptable) excipient, or physiologically suitable (or acceptable)carrier) selected on the basis of a chosen route of administration andstandard pharmaceutical practice as described, for example, inRemington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)), the disclosure of which is herebyincorporated herein by reference in its entirety.

Accordingly, provided herein is a pharmaceutical composition comprisingat least one substituted imidazole-pyridine derivative compound, or astereoisomer, pharmaceutically acceptable salt, hydrate, solvate, orN-oxide thereof, together with one or more pharmaceutically acceptablecarriers. The carrier(s) (or excipient(s)) is acceptable or suitable ifthe carrier is compatible with the other ingredients of the compositionand not deleterious to the recipient (i.e., the subject) of thecomposition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I), or apharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (II), or apharmaceutically acceptable salt thereof.

In certain embodiments, the substituted imidazole-pyridine derivativecompound as described by Formula (I) or (II) is substantially pure, inthat it contains less than about 5%, or less than about 1%, or less thanabout 0.1%, of other organic small molecules, such as contaminatingintermediates or by-products that are created, for example, in one ormore of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. (See, e.g., Remington: The Science and Practiceof Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one substitutedimidazole-pyridine derivative compound as described herein may differ,depending upon the patient's (e.g., human) condition, that is, stage ofthe disease, general health status, age, and other factors that a personskilled in the medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

Oral doses can typically range from about 1.0 mg to about 1000 mg, oneto four times, or more, per day.

Histone Demethylase

Chromatin is the complex of DNA and protein that makes up chromosomes.Histones are the major protein component of chromatin, acting as spoolsaround which DNA winds. Changes in chromatin structure are affected bycovalent modifications of histone proteins and by non-histone bindingproteins. Several classes of enzymes are known which can covalentlymodify histones at various sites.

Proteins can be post-translationally modified by methylation on aminogroups of lysines and guanidino groups of arginines or carboxymethylatedon aspartate, glutamate, or on the C-terminus of the protein.Post-translational protein methylation has been implicated in a varietyof cellular processes such as RNA processing, receptor mediatedsignaling, and cellular differentiation. Post-translational proteinmethylation is widely known to occur on histones, such reactions knownto be catalyzed by histone methyltransferases, which transfer methylgroups from S-adenosyl methionine (SAM) to histones. Histone methylationis known to participate in a diverse range of biological processesincluding heterochromatin formation, X-chromosome inactivation, andtranscriptional regulation (Lachner et al., (2003) J. Cell Sci.116:2117-2124; Margueron et al., (2005) Curr. Opin. Genet. Dev.15:163-176).

Unlike acetylation, which generally correlates with transcriptionalactivation, whether histone methylation leads to transcriptionactivation or repression depends on the particular site of methylationand the degree of methylation (e.g., whether a particular histone lysineresidue is mono-, di-, or tri-methylated). However, generally,methylation on H3K9, H3K27 and H4K20 is linked to gene silencing, whilemethylation on H3K4, H3K36, and H3K79 is generally associated withactive gene expression. In addition, tri- and di-methylation of H3K4generally marks the transcriptional start sites of actively transcribedgenes, whereas mono-methylation of H3K4 is associated with enhancersequences.

A “demethylase” or “protein demethylase,” as referred to herein, refersto an enzyme that removes at least one methyl group from an amino acidside chain. Some demethylases act on histones, e.g., act as a histone H3or H4 demethylase. For example, an H3 demethylase may demethylate one ormore of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4demethylase may demethylate histone H4K20. Demethylases are known whichcan demethylate either a mono-, di- and/or a tri-methylated substrate.Further, histone demethylases can act on a methylated core histonesubstrate, a mononucleosome substrate, a dinucleosome substrate and/oran oligonucleosome substrate, peptide substrate and/or chromatin (e.g.,in a cell-based assay).

The first lysine demethylase discovered was lysine specific demethylase1 (LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 orH3K9, using flavin as a cofactor. A second class of Jumonji C (JmjC)domain containing histone demethylases were predicted, and confirmedwhen a H3K36 demethylase was found using a formaldehyde release assay,which was named JmjC domain containing histone demethylase 1(JHDM1/KDM2A).

More JmjC domain-containing proteins were subsequently identified andthey can be phylogenetically clustered into seven subfamilies: JHDM1,JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.

FBXL10 and FBXL11

F-box and leucine-rich repeat protein 10 (FBXL10) and F-box andleucine-rich repeat protein 11 (FBXL11) are multifunctional F-box familyproteins that demethylate histone H3 through a hydroxylation basedmechanism. FBXL10, also known as lysine (K)-specific demethylase 2B(KDM2B) or Jumonji C domain-containing histone demethylase 1B (JHDM1B),preferentially demethylates trimethylated K4 and dimethylated K36 ofhistone H3, but contains weak or no activity for mono- andtri-methylated H3K36. FBXL10 contains three domains, a catalytic JMJCdomain, an F-box domain and a CXXC DNA-binding domain. The N-terminalJMJC domain coordinates iron and α-ketoglutarate to catalyzedemethylation through the hydroxylation based mechanism. The CXXCDNA-binding domain allows FBXL10 to preferentially bind to transcribedregion of the ribosomal RNA, leading to repression of the ribosomal RNAgene transcription and ultimately leading to inhibition of cell growthand proliferation. FBXL10 has been found to be overexpressed in acutemyeloid leukemia, bladder carcinoma and pancreatic ductaladenocarcinoma. Recently, it has been demonstrated that FBXL10 regulatesthe expression of Polycomb target genes, those proteins are epigeneticregulators essential for stem cell differentiation. This regulationimplicates FBXL10's involvement in tumorigenesis through the regulationof these Polycomb target genes.

FBXL11, also known as KDM2A or JHDM1A, demethylates mono- anddi-methylated K36 of histone H3. The CXXC DNA-binding domain recognizesnon-methylated DNA and targets CpG island regions where it specificallyremoves H3K36 methylation. Further, FBXL11 is required to maintain aheterochromatic state, sustain centromeric integrity and genomicstability during mitosis. In addition, FBXL11 is a key negativeregulator of NF-KB. Overexpression of FBXL11 has been observed innon-small cell lung cancer (NSCLC) where FBXL11 upregulatesphosphor-ERK1/2 by repressing DUSP3 expression in NSCLC cell lines.Negative regulation of gluconeogenic gene expression by FBXL11 resultsin suppression of two rate-limiting gluconeogenic enzymes, critical formaintaining blood glucose homeostasis.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (I) or (II).

In an additional embodiment is the method for inhibiting ahistone-demethylase enzyme, wherein the histone-demethylase enzymecomprises a JmjC domain. In an additional embodiment is the method forinhibiting a histone-demethylase enzyme, wherein the histone-demethylaseenzyme is selected from FBXL10 or FBXL11.

Methods of Treatment

Disclosed herein are methods of modulating demethylation in a cell or ina subject, either generally or with respect to one or more specifictarget genes. Demethylation can be modulated to control a variety ofcellular functions, including without limitation: differentiation;proliferation; apoptosis; tumorigenesis, leukemogenesis or otheroncogenic transformation events; hair loss; or sexual differentiation.For example, in particular embodiments, the invention provides a methodof treating a disease regulated by histone methylation and/ordemethylation in a subject in need thereof by modulating the activity ofFBXL10 or FBXL11.

In an additional embodiment is a method for treating cancer in subjectcomprising administering a composition comprising a compound of Formula(I) or (II), or a pharmaceutically acceptable salt thereof.

In a further embodiment is the method for treating cancer in a subjectwherein the cancer is selected from pancreatic cancer, prostate cancer,breast cancer, gastric cancer, leukemia, bladder cancer, lung cancer ormelanoma.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

Examples I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Preparation 1A: 2-(1-methylimidazol-4-yl)pyridine-4-carbonitrile

A mixture of 2-chloro-4-pyridinenitrile (1.85 g, 13.4 mmol),N-methyl-4-(tributylstannyl)imidazole (5 g, 13.4 mmol) and Pd(PPh₃)₄(1.42 g, 1.34 mmol) in DMF (50 mL) was stirred for 3 hr at 130° C. underN₂. The mixture was concentrated and purified by flash columnchromatography on silica gel (CH₂Cl₂/MeOH=20/1) to afford the titlecompound (2.0 g, 80%). [M+H] Calc'd for C₁₀H₅N₄, 185; Found, 185.

Preparation 1B:trimethyl-[4-[2-(1-methylimidazol-4-yl)pyridin-4-yl]-1H-triazol-5-yl]silane

To a solution of TMSCHN₂ (0.76 mL, 1.52 mmol) in THF was added n-BuLi(0.60 mL, 1.52 mmol) at 0° C., stirred for 20 min, then a solution of2-(1-methylimidazol-4-yl)pyridine-4-carbonitrile (200 mg, 1.09 mmol) inTHF was added, and the reaction mixture was stirred overnight at rt.LC/MS showed the reaction was completed, sat. NH₄Cl was added andextracted with EtOAc, dried, concentrated to give the title compound(296 mg, 90%). [M+H] Calc'd for C₁₄H₁₈N₆Si, 299; Found, 299.

Example 1: 2-(1-methylimidazol-4-yl)-4-(1H-triazol-4-yl)pyridine

A mixture oftrimethyl-[4-[2-(1-methylimidazol-4-yl)pyridin-4-yl]-1H-triazol-5-yl]silane(296 mg, 0.99 mmol) and NaOH (2.2 mL, 4.46 mmol, 2M) in MeOH was stirredovernight at 50° C. LC/MS showed the reaction was completed, H₂O wasadded, extracted with ethyl acetate, dried, purified by HPLC to give thetitle compound (38 mg, 18%) as a yellow solid. ¹H NMR (300 MHz, CD₃OD):δ 3.99 (3H, s), 7.96 (1H, dd, J=5.4 Hz, J=1.2 Hz), 8.21 (1H, d, J=0.6Hz), 8.46 (1H, s), 8.47-8.64 (1H, m), 8.65 (1H, s), 8.69 (1H, d, J=5.4Hz). [M+H] Calc'd for C₁₁H₁₀N₆, 227; Found, 227.

Preparation 2A:2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carboxamide

A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (1 g, 5.32mmol), 1-bromomethyl-2-chloro-benzene (2.17 g, 10.64 mmol) and K₂CO₃(1.47 g, 10.64 mmol) in DMF (50 mL) was stirred overnight at rt. LC/MSshowed the reaction was completed. The mixture was concentrated andpurified by flash column chromatography on silica gel (CH₂Cl₂/MeOH=20/1)to afford the title compound (1.2 g, 66%). [M+H] Calc'd for C₁₆H₁₃ClN₄O,313; Found, 313.

Preparation 2B:2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbonitrile

To a solution of2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carboxamide (1.2g, 3.54 mmol) and pyridine (0.91 g, 10.64 mmol) in CH₂Cl₂ was addedtrifluoroacetic acid anhydride (1.62 g, 7.08 mmol) at 0° C., which wasthen stirred for 2 hr at 0° C. LC/MS showed the reaction was completed.H₂O was added and extracted with CH₂Cl₂, the organic layer was washed byaqueous NaHCO₃ and brine, dried, concentrated and purified by flashcolumn chromatography on silica gel (PE/EA=1/3) to give the titlecompound (844 mg, 74%). [M+H] Calc'd for C₁₆H₁₁ClN₄, 295; Found, 295.

Preparation 2C:[4-[2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]-1H-triazol-5-yl]-trimethylsilane

The title compound was prepared in 98% yield according to the procedureof Preparation 1B. [M+H] Calc'd for C₂₀H₂₁ClN₆Si, 409; Found, 409.

Example 2:2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 44% yield according to the procedureof last step of Example 1. ¹H NMR (300 MHz, CD₃OD): δ 5.58 (2H, s),7.44-7.54 (4H, m), 8.03 (1H, d, J=5.7 Hz), 8.22 (1H, s), 8.55-8.65 (4H,m). [M+H] Calc'd for C₁₇H₁₃ClN₆, 337; Found, 337.

Preparation 3A: 2-(5-bromo-1-methylimidazol-4-yl)pyridine-4-carbonitrile

To a solution of 2-(1-methylimidazol-4-yl)pyridine-4-carbonitrile (600mg, 3.26 mmol, Preparation 1A) in CH₂Cl₂ (30 mL), was added NBS (610 mg,3.42 mmol) and it was stirred for 3 hr at rt. Washed by H₂O, dried andconcentrated to afford the title compound (810 mg, 95%). [M+H] Calc'dfor C₁₀H₇BrN₄, 263; Found, 263.

Preparation 3B:2-[5-(4-fluorophenyl)-1-methylimidazol-4-yl]pyridine-4-carbonitrile

A mixture of 2-(5-bromo-1-methylimidazol-4-yl)pyridine-4-carbonitrile (1eq), 4-fluorophenylboronic acid (1.2 eq), Pd(dppf)Cl₂ (0.1 eq) and 2MNa₂CO₃ (2 eq) in dioxane was refluxed overnight under N₂, concentratedand purified by flash column chromatography (DCM/MeOH=20/1) to give thetitle compound (140 mg, 50%). [M+H] Calc'd for C₁₆H₁₁FN₄, 279; Found,279.

Preparation 3C:[4-[2-[5-(4-fluorophenyl)-1-methylimidazol-4-yl]pyridin-4-yl]-1H-triazol-5-yl]-trimethylsilane

The title compound was prepared in 87% yield according to the procedureof Preparation 1B. [M+H] Calc'd for C₂₀H₂₁FN₆Si, 393; Found, 393.

Example 3:2-[5-(4-fluorophenyl)-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 12% yield according to the procedureof last step of Example 1. ¹H NMR (300 MHz, DMSO+CD₃OD): δ 3.61 (3H, s),7.44-7.85 (6H, m), 8.30 (1H, s), 8.64 (1H, d, J=5.4 Hz), 8.84-8.85 (1H,m). [M+H] Calc'd for C₁₇H₁₃FN₆, 321; Found, 321.

Preparation 4A:2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 25% yield according to the procedureof Preparation 3B. [M+H] Calc'd for C₂₀H₁₇FN₄O, 349; Found, 349.

Preparation 4B:[4-[2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]-1H-triazol-5-yl]-trimethylsilane

The title compound was prepared in 25% yield according to the procedureof Preparation 1B. [M+H] Calc'd for C₂₄H₂₇FN₆OSi, 463; Found, 463.

Example 4:2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 13% yield according to the procedureof last step of Example 1. ¹H NMR (300 MHz, DMSO+CD₃OD): δ 0.10-0.36(4H, m), 0.91-0.98 (1H, m), 3.37 (3H, s), 3.72-3.82 (2H, m), 6.80-6.81(1H, m), 6.97 (1H, d, J=10.5 Hz), 7.28 (1H, t, J=3.6 Hz), 7.52 (1H, d,J=4.8 Hz), 7.86 (1H, s), 8.25-8.33 (3H, m). [M+H] Calc'd for C₂₁H₁₉FN₆O,391; Found, 391.

Example 5:2-[1-(1-phenylethyl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 6% overall yield according to theprocedure of Example 2 starting from2-(1H-imidazol-4-yl)pyridine-4-carboxamide. ¹H NMR (300 MHz, CD₃OD): δ1.94 (3H, d, J=14.1 Hz), 5.58-5.65 (1H, m), 7.32-7.44 (5H, m), 7.75 (1H,d, J=5.1 Hz), 7.83 (1H, s), 7.94 (1H, s), 8.39 (2H, s), 8.52 (1H, d,J=5.1 Hz). [M+H] Calc'd for C₁₈H₁₆N₆, 317; Found, 317.

Preparation 6A:2-[1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]pyridine-4-carboxamide

A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (500 mg, 2.66mmol), 1-(2-bromo-ethyl)-2-chloro-benzene (2.32 g, 10.64 mmol) and K₂CO₃(1.47 g, 10.64 mmol) in DMF (20 mL) was stirred overnight at 100° C.LC/MS showed the reaction was completed. The reaction mixture waspurified by flash column chromatography to give the title compound (300mg, 34%) as a yellow solid. [M+H] Calc'd for C₁₇H₁₅ClN₄O, 327; Found,327.

Preparation 6B:2-[1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]pyridine-4-carbonitrile

The title compound was prepared in 77% yield according to the procedureof Preparation 2B. [M+H] Calc'd for C₁₇H₁₃ClN₄, 309; Found, 309.

Preparation 6C:[4-[2-[1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]pyridin-4-yl]-1H-triazol-5-yl]-trimethylsilane

The title compound was prepared in 100% yield according to the procedureof Preparation 1B. [M+H] Calc'd for C₂₁H₂₃ClN₆Si, 423; Found, 423.

Example 6:2-[1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 42% yield according to the procedureof last step of Example 1. ¹H NMR (300 MHz, CD₃OD): δ 3.23 (2H, t, J=7.2Hz), 4.31 (2H, t, J=7.2 Hz), 7.25-7.28 (3H, m), 7.44-7.47 (1H, m),7.63-7.64 (2H, m), 7.79 (1H, s), 8.30 (1H, s), 8.53 (1H, d, J=5.1 Hz),8.62 (1H, s). [M+H] Calc'd for C₁₈H₁₅ClN₆, 351; Found, 351.

Example 7:2-[1-[2-(2-methoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 12% overall yield according to theprocedure of Example 6 starting from2-(1H-imidazol-4-yl)pyridine-4-carboxamide. ¹H NMR (300 MHz, CD₃OD): δ3.14 (2H, t, J=6.9 Hz), 3.82 (3H, s), 4.32 (2H, t, J=6.9 Hz), 6.81-7.22(4H, m), 7.52 (1H, s), 7.68 (1H, s), 7.73 (1H, d, J=5.4 Hz), 8.32 (1H,s), 8.37 (1H, s), 8.52 (1H, d, J=5.4 Hz). [M+H] Calc'd for C₁₉H₁₈N₆O,347; Found, 347.

Example 8:2-[1-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 12% overall yield according to theprocedure of Example 6 starting from2-(1H-imidazol-4-yl)pyridine-4-carboxamide. ¹H NMR (300 MHz, DMSO): δ1.45-1.85 (4H, m), 2.69-2.74 (2H, m), 3.28-3.34 (1H, m), 4.11-4.35 (2H,m), 7.09-7.16 (3H, m), 7.28-7.31 (1H, m), 7.65 (1H, d, J=5.4 Hz), 7.77(1H, s), 7.88 (1H, s), 8.34 (1H, s), 8.84 (1H, d, J=5.4 Hz), 8.34 (1H,s). [M+H] Calc'd for C₂₁H₂₀N₆, 357; Found, 357.

Preparation 9A:2-[1-[2-(2-ethoxyphenyl)ethyl]imidazol-4-yl]pyridine-4-carboxamide

A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (1 eq), ROMs(1.2 eq) and K₂CO₃ (2 eq) in DMF (50 mL) was stirred overnight at 80° C.LC/MS showed the reaction was completed. The mixture was concentratedand purified by flash column chromatography on silica gel(DCM/MeOH=20/1) to afford the title compound. [M+H] Calc'd forC₁₉H₂₀N₄O₂, 337; Found, 337.

Preparation 9B:2-[1-[2-(2-ethoxyphenyl)ethyl]imidazol-4-yl]pyridine-4-carbonitrile

The title compound was prepared in 60% yield according to the procedureof Preparation 2B. [M+H] Calc'd for C₁₉H₁₈N₄O, 319; Found, 319.

Preparation 9C:[4-[2-[1-[2-(2-ethoxyphenyl)ethyl]imidazol-4-yl]pyridin-4-yl]-1H-triazol-5-yl]-trimethylsilane

The title compound was prepared in 100% yield according to the procedureof Preparation 1B. [M+H] Calc'd for C₂₃H₂₈N₆OSi, 433; Found, 433.

Example 9:2-[1-[2-(2-ethoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 54% yield according to the procedureof the last step of Example 1. ¹H NMR (300 MHz, DMSO): δ 1.36 (3H, t,J=6.9 Hz), 3.06 (2H, t, J=6.9 Hz), 4.02 (2H, q, J=6.9 Hz), 4.25 (2H, t,J=6.9 Hz), 6.79-7.22 (4H, m), 7.59 (1H, s), 7.63 (1H, d, J=4.2 Hz), 7.72(1H, s), 8.30 (1H, s), 8.53 (1H, d, J=5.4 Hz), 8.62 (1H, s). [M+H]Calc'd for C₂₀H₂₀N₆O, 361; Found, 361.

Example 10:4-(1H-triazol-4-yl)-2-[1-[2-[2-(2,2,2-trifluoroethoxy)phenyl]ethyl]imidazol-4-yl]pyridine

The title compound was prepared in 11% overall yield according to theprocedure of Example 9 starting from2-(1H-imidazol-4-yl)pyridine-4-carboxamide. ¹H NMR (300 MHz, DMSO): δ3.10 (2H, t, J=7.2 Hz), 4.25 (2H, t, J=7.2 Hz), 4.81 (2H, q, J=9.0 Hz),6.93-7.26 (4H, m), 7.56 (1H, s), 7.63 (1H, d, J=4.5 Hz), 7.71 (1H, s),8.30 (1H, s), 8.53 (1H, d, J=4.8 Hz), 8.64 (1H, m). [M+H] Calc'd forC₂₀H₁₇F₃N₆O, 415; Found, 415.

Example 11:2-[1-[2-[2-(cyclopropylmethoxy)phenyl]ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 3% overall yield according to theprocedure of Example 9 starting from2-(1H-imidazol-4-yl)pyridine-4-carboxamide. ¹H NMR (300 MHz, DMSO): δ0.36-0.37 (2H, m), 0.57-0.60 (2H, m), 1.30-1.35 (1H, m), 3.07 (2H, t,J=6.9 Hz), 3.85 (2H, d, J=5.7 Hz), 4.47 (2H, t, J=6.6 Hz), 6.81-7.18(4H, m), 7.60-7.63 (2H, m), 7.74 (1H, s), 8.30 (1H, s), 8.52-8.53 (2H,m). [M+H] Calc'd for C₂₂H₂₂N₆O, 387; Found, 387.

Example 12:2-[1-(3,4-dihydro-2H-chromen-4-ylmethyl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 4% overall yield according to theprocedure of Example 9 starting from2-(1H-imidazol-4-yl)pyridine-4-carboxamide. ¹H NMR (300 MHz, DMSO): δ1.64-1.83 (2H, m), 3.30-3.33 (1H, m), 4.13-4.46 (4H, m), 6.77-6.90 (2H,m), 7.11-7.26 (2H, m), 7.65 (1H, d, J=5.7 Hz), 7.80 (1H, s), 7.92 (1H,s), 8.34 (1H, s), 8.55 (1H, d, J=5.7 Hz), 8.64 (1H, m). [M+H] Calc'd forC₂₀H₁₈N₆O, 359; Found, 359.

Preparation 13A:2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carboxylic acid

A mixture of2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbonitrile (430mg, 1.46 mmol, Preparation 2B) and NaOH (1.5 mL, 7.31 mmol, 5M) in EtOHwas refluxed overnight. LC/MS showed the reaction was completed, cooledto rt and acidified to pH=3-4 by 1N HCl, the solid was collected, driedto give the title compound (424 mg, 92%). [M+H] Calc'd for C₁₆H₁₂ClN₃O₂,314; Found, 314.

Preparation 13B:[2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]methanol

To a solution of2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carboxylic acid(424 mg, 1.34 mmol) in THF was added a solution of LiAlH₄ in THF (1.8mL, 4.43 mmol, 2.4 M) at 0° C., then stirred for 2 hr at rt. LC/MSshowed the reaction was completed. 0.1 mL H₂O, 0.1 mL NaOH, and 0.3 mLH₂O was added subsequently, filtered, concentrated to give the titlecompound (405 mg, 100%). [M+H] Calc'd for C₁₆H₁₄ClN₃O, 300; Found, 300.

Preparation 13C:2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbaldehyde

To a solution of Dess-Martin oxidant (640 mg, 1.5 mmol) in THF (20 mL)was added a solution of[2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]methanol (300mg, 1.0 mmol) at 0° C. The reaction mixture was stirred for 2 hr at rt.LC/MS showed the reaction was completed. NaOH (42 mL, 42 mmol) was addedto quench the reaction. It was then extracted by EtOAc, dried andconcentrated to give the title compound (300 mg, 61%). [M+H] Calc'd forC₁₆H₁₂ClN₃O, 298; Found, 298.

Preparation 13D:2-(benzenesulfonyl)-3-[2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]prop-2-enenitrile

A mixture of2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbaldehyde (100mg, 0.33 mmol), 2-(benzenesulfonyl)acetonitrile (60 mg, 0.33 mmol) andNaHCO₃ (1.64 mL, 0.41 mmol, 0.25 M) in EtOH was stirred overnight at rt.LC/MS showed the reaction was completed, concentrated and purified bypreparative TLC (DCM/MeOH=20/1) to give the title compound (40 mg, 26%).[M+H] Calc'd for C₂₄H₁₇ClN₄O₂S, 461; Found, 461.

Example 13:4-[2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile

A mixture of2-(benzenesulfonyl)-3-[2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]prop-2-enenitrile(40 mg, 0.086 mmol, Preparation 13D) and NaN₃ (6 mg, 0.086 mmol) in DMFwas stirred for 2 hr at 100° C. LC/MS showed the reaction was completed,acidified to pH=3-4 by 1N HCl, and stirred for 30 min, then adjusted topH=7-8 by 1N NaOH, concentrated and purified by prep-HPLC to give thetitle compound (12 mg, 39%). ¹H NMR (400 MHz, CD₃OD): δ 5.64 (2H, s),7.46-7.53 (4H, m), 7.92 (1H, d, J=5.6 Hz), 8.20 (1H, s), 8.35 (1H, s),8.74 (1H, d, J=5.2 Hz), 9.01 (1H, s). [M+H] Calc'd for C₁₈H₁₂ClN₇, 362;Found, 362.

Example 14:4-[2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile

The title compound was prepared in 3% overall yield according to theprocedure of Example 13 starting from2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbonitrile.¹H NMR (300 MHz, DMSO): δ 5.43 (2H, s), 7.12-7.15 (1H, m), 7.37-7.43(1H, m), 7.60-7.93 (4H, m), 8.41-8.49 (2H, m). [M+H] Calc'd forC₁₈H₁₁Cl₂N₇, 396; Found, 396.

Example 15:4-[2-[1-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile

The title compound was prepared in 2% overall yield according to theprocedure of Example 13 starting from2-[1-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)imidazol-4-yl]pyridin-4-carbonitrile.¹H NMR (400 MHz, CD₃OD): δ 1.77-1.95 (4H, m), 2.84-2.86 (2H, m),3.10-3.11 (1H, m), 4.49-4.60 (2H, m), 7.13-7.20 (4H, m), 8.06 (1H, d,J=4.8 Hz), 8.41 (1H, s), 8.46 (1H, s), 8.90 (1H, d, J=5.2 Hz), 9.01 (1H,s). [M+H] Calc'd for C₂₂H₁₉N₇, 382; Found, 382.

Example 16:4-[2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile

The title compound was prepared in 2% overall yield according to theprocedure of Example 13 starting from2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridin-4-carbonitrile. ¹HNMR (300 MHz, CD₃OD): δ 3.75-3.77 (2H, m), 4.70-4.72 (2H, m), 7.31-7.57(4H, m), 7.82-8.14 (4H, m), 8.27 (1H, s), 8.35 (1H, s), 8.72 (1H, s),8.85 (1H, s). [M+H] Calc'd for C₂₃H₁₇N₇, 392; Found, 392.

Preparation 17a: 2-(2-phenylmethoxyphenyl)ethanol

A mixture of 2-(2-hydroxyethyl)phenol (1 g, 7.2 mmol),bromomethylbenzene (1.35 g, 7.92 mmol) and K₂CO₃ (2 g, 14.5 mmol) wasstirred overnight at 90° C. H₂O was added, extracted with ethylacetate,purified by flash column chromatography on silica gel (PE/EA=1/1) toafford the title compound (1.48 g, 90%). [M+H] Calc'd for C₁₅H₁₆O₂, 229;Found, 229.

Preparation 17b: 2-(2-phenylmethoxyphenyl)ethyl methanesulfonate

To a solution of 2-(2-phenylmethoxyphenyl)ethanol (1.48 g, 6.48 mmol)and triethylamine (1.31 g, 13 mmol) in CH₂Cl₂ (20 mL) was added MsCl(1.11 g, 9.7 mmol) at 0° C., then stirred for 2 hr at rt, washed by H₂O,dried, concentrated to give the title compound (1.6 g, 81%) which wasused directly for next step. [M+H] Calc'd for C₁₆H₁₈O₄S, 307; Found,307.

Example 17:2-[1-[2-(2-phenylmethoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 4% overall yield according to theprocedure of Example 9 starting from 2-(2-phenylmethoxyphenyl)ethylmethanesulfonate and 2-(1H-imidazol-4-yl)pyridine-4-carboxamide. ¹H NMR(300 MHz, DMSO): δ 3.11 (2H, t, J=6.9 Hz), 4.26 (2H, t, J=6.9 Hz), 5.16(2H, s), 6.83-7.74 (12H, m), 8.30 (1H, s), 8.54-8.64 (2H, m). [M+H]Calc'd for C₂₅H₂₂N₆O, 423; Found, 423.

Preparation 18a: 2-(2-phenoxyphenyl)ethanol

A mixture of 2-(2-hydroxyethyl)phenol (1 g, 7.2 mmol), bromobenzene(1.70 g, 10.8 mmol), 1-pyridin-2-yl-propan-2-one (194 mg, 1.44 mmol),CuBr (103 mg, 0.72 mmol) and Cs₂CO₃ (4.73 g, 14.5 mmol) in DMSO (20 mL)was stirred overnight at 80° C., H₂O was added, extracted with EtOAc,purified by flash column chromatography on silica gel (PE/EA=1/1) toafford the title compound (850 mg, 54%). [M+H] Calc'd for C₁₄H₁₄O₂, 215;Found, 215.

Preparation 18b: 2-(2-phenoxyphenyl)ethyl methanesulfonate

The title compound was prepared in 100% yield according to the procedureof Preparation 17b. [M+H] Calc'd for C₁₅H₁₆O₄S, 293; Found, 293.

Example 18:2-[1-[2-(2-phenoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 8% overall yield according to theprocedure of Example 9 starting from 2-(2-phenoxyphenyl)ethylmethanesulfonate and 2-(1H-imidazol-4-yl)pyridine-4-carboxamide. ¹H NMR(300 MHz, DMSO): δ 3.10 (2H, t, J=6.9 Hz), 4.29 (2H, t, J=6.9 Hz),6.83-7.34 (9H, m), 7.59 (1H, s), 7.63 (1H, d, J=5.1 Hz), 7.72 (1H, s),8.30 (1H, s), 8.52 (1H, d, J=5.1 Hz), 8.64 (1H, s). [M+H] Calc'd forC₂₄H₂₀N₆O, 409; Found, 409.

Preparation 19A:2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbaldehyde

The title compound was prepared in 19% overall yield according to theprocedures of Preparation 13A-13C starting from2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]pyridine-4-carboxamide.[M+H] Calc'd for C₁₆H₁₁Cl₂N₃O, 332; Found, 332.

Preparation 19B:2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-ethynylpyridine

A mixture of2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbaldehyde(330 mg, 1.0 mmol) and K₂CO₃ (276 mg, 2.0 mmol) in MeOH (20 mL) wasstirred for 15 min at rt, then (1-diazo-2-oxo-propyl)-phosphonic aciddimethyl ester (470 mg, 2.4 mmol) was added and stirred for 2 hr at rt.LC/MS showed the reaction was completed, concentrated and purified byflash column chromatography on silica gel (CH₂Cl₂/MeOH=20/1) to affordthe title compound (260 mg, 79%). [M+H] Calc'd for C₁₇H₁₁Cl₂N₃, 328;Found, 328.

Preparation 19C:2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]pyridine

A mixture of 1-(azidomethyl)-4-methoxybenzene (310 mg, 1.86 mmol), KI(617 mg, 3.72 mmol) and Cu(ClO₄)₂.6H₂O (1.376 g, 3.72 mmol) in THF wasstirred for 5 min at rt. Then triethylamine (375 mg, 3.72 mmol) and2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-ethynylpyridine (610mg, 1.86 mmol) were added sequentially and stirred for 1 h at rt. LC/MSshowed the reaction was completed, diluted with EtOAc, washed by 25%NH₃—H₂O, dried and concentrated to give the title compound (916 mg,80%). [M+H] Calc'd for C₂₅H₁₉Cl₂IN₆O, 617; Found, 617.

Example 19:2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(5-iodo-1H-triazol-4-yl)pyridine

A solution of2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]pyridine(50 mg, 0.08 mmol) in TFA (3 ml) was stirred for 5 hr at 65° C. LC/MSshowed the reaction was completed, concentrated and purified byprep-HPLC to give the title compound (10 mg, 25%). ¹H NMR (400 MHz,CD₃OD): δ 5.62 (2H, s), 7.40-7.42 (2H, m), 7.63-7.66 (1H, m), 8.14-8.16(1H, m), 8.23 (1H, s), 8.57 (1H, s), 8.69-8.72 (2H, m). [M+H] Calc'd forC₁₇H₁₁Cl₂IN₆, 497; Found, 497.

Preparation 20A:2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-[5-fluoro-1-[(4-methoxyphenyl)methyl]triazol-4-yl]pyridine

A mixture of2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]pyridine(70 mg, 0.11 mmol, Preparation 19C) and KF (33 mg, 0.55 mmol) in ACN/H₂O(2 ml/2 ml) was stirred for 10 min at 160° C. in a microwave oven. LC/MSshowed the reaction was completed, H₂O was added, extracted with EtOAc,dried to give the title compound (46 mg, 80%) as a yellow solid. [M+H]Calc'd for C₂₅H₁₉Cl₂FN₆O, 509; Found, 509.

Example 20:2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(5-fluoro-1H-triazol-4-yl)pyridine

The title compound was prepared in 13% yield according to the procedureof last step of Example 19. ¹H NMR (300 MHz, CD₃OD): δ 5.58 (2H, s),7.36-7.41 (2H, m), 7.60-7.62 (1H, m), 7.81-7.82 (1H, m), 8.18-8.25 (2H,m), 8.39 (1H, s), 8.41 (1H, s). [M+H] Calc'd for C₁₇H₁₁Cl₂FN₆, 389;Found, 389.

Preparation 21A: 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile

A mixture of 2-chloro-4-pyridinenitrile (661 mg, 4.77 mmol),4-(tributylstannyl)-1-tritylimidazole (3 g, 5 mmol) and Pd(PPh₃)₄ (276mg, 0.24 mmol) in toluene (20 mL) was heated in a microwave oven for 2hr at 120° C. The mixture was concentrated and purified by flash columnchromatography on silica gel (EtOAc/hexane) to give the trityl protectedproduct. It was then treated with HOAc/TFA (4 mL/5 mL) for 2 hrs.Purification by flash column chromatography gave the title compound (800mg, 98%). [M+H] Calc'd for C₉H₆N₄, 171; Found, 171.

Example 21:2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 40% yield starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A) accordingto the procedure of Example 2. ¹H NMR (400 MHz, DMSO-d6): δ 5.45 (2H,s), 7.13 (1H, d, J=6.7 Hz), 7.40 (1H, t, J=7.9 Hz), 7.63 (1H, br s),7.65 (1H, d, J=8 Hz), 7.82 (1H, s), 7.93 (1H, s), 8.63 (1H, d, J=5.1Hz), 8.96 (1H, br s). [M+H] Calc'd for C₁₇H₁₂Cl₂N₆, 371; Found, 371.

Example 22:2-[1-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 4% yield starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A) accordingto the procedure of Example 2. ¹H NMR (400 MHz, DMSO-d6): δ 5.52 (2H,s), 7.43 (1H, d, J=8.0 Hz), 7.59 (1H, t, J=7.9 Hz), 7.65 (1H, d, J=3.4Hz), 7.86 (1H, d, J=6.7 Hz), 7.95 (1H, s), 8.35 (1H, s), 8.53 (2H, d,J=5.0 Hz). [M+H] Calc'd for C₁₈H₁₂ClF₃N₆, 405; Found, 405.

Example 23:2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 11% yield starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A) accordingto the procedure of Example 6. ¹H NMR (400 MHz, DMSO-d6): δ 3.60 (2H, t,J=6.8 Hz), 4.39 (2H, t, J=6.9 Hz), 7.36 (1H, d, J=7.0 Hz), 7.42 (1H, t,J=7.0 Hz), 7.53-7.64 (3H, m), 7.69 (1H, s), 7.82 (1H, d, J=8.3 Hz), 7.91(1H, s), 7.94 (1H, d, J=7.8 Hz), 8.24 (1H, d, J=8.4 Hz), 8.31 (1H, s),8.53 (1H, d, J=4.9 Hz), 8.62 (1H, s). [M+H] Calc'd for C₂₂H₁₈N₆, 367;Found, 367.

Example 24:2-[5-(4-fluoro-3-methoxyphenyl)-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 20% yield according to the procedureof Example 3 starting from2-(5-bromo-1-methylimidazol-4-yl)pyridine-4-carbonitrile (Preparation3A). ¹H NMR (400 MHz, DMSO-d6): δ 3.53 (3H, s), 3.82 (3H, s), 6.98-7.01(1H, m), 7.23-7.30 (2H, m), 7.56 (1H, dd, J=5.0 and 1.6 Hz), 7.86 (1H,s), 8.18 (1H, s), 8.32 (1H, d, J=5.1 Hz), 8.35 (1H, s), 8.56 (1H, s).[M+H] Calc'd for C₁₈H₁₅FN₆O, 351; Found, 351.

Example 25:2-[5-(3-ethoxy-4-fluorophenyl)-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 16% yield according to the procedureof Example 3 starting from2-(5-bromo-1-methylimidazol-4-yl)pyridine-4-carbonitrile (Preparation3A). ¹H NMR (400 MHz, DMSO-d6): δ 1.32 (3H, t, J=7.0 Hz), 3.50 (3H, s),4.08 (2H, q, J=6.9 Hz), 6.96-7.00 (1H, m), 7.23-7.28 (2H, m), 7.56 (1H,dd, J=5.1 and 1.7 Hz), 7.86 (1H, s), 8.18 (1H, s), 8.32 (1H, d, J=5.1Hz), 8.34 (1H, s), 8.56 (1H, s). [M+H] Calc'd for C₁₉H₁₇FN₆O, 365;Found, 365.

Example 26:2-[1-[[2-fluoro-3-(trifluoromethoxy)phenyl]methyl]imidazol-44-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 17% yield starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A) accordingto the procedure of Example 2. ¹H NMR (400 MHz, DMSO-d6): δ 5.45 (2H,s), 7.34-7.36 (2H, m), 7.55-7.57 (1H, m), 7.64-7.66 (1H, m), 7.81 (1H,s), 7.92 (1H, s), 8.25 (1H, s), 8.33 (1H, s), 8.52 (1H, d, J=5.1 Hz),8.61 (1H, br s). [M+H] Calc'd for C₁₈H₁₂F₄N₆O, 405; Found, 405.

Example 27:2-[1-[2-(2-phenylphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 4% overall yield according to theprocedure of Example 6 starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A). ¹H NMR(400 MHz, DMSO-d6): δ 3.04 (2H, t, J=7.3 Hz), 4.13 (2H, t, J=7.2 Hz),7.20 (1H, m), 7.21-7.31 (5H, m), 7.33-7.47 (4H, m), 7.54 (1H, dd, J=5.4and 1.6 Hz), 7.62 (1H, dd, J=5.1 and 1.6 Hz), 8.27 (1H, s), 8.32 (1H,s), 8.59 (1H, s). [M+H] Calc'd for C₂₄H₂₀N₆, 393; Found, 393.

Example 28:2-[1-[(2-fluoro-3-methylphenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridin

The title compound was prepared in 7% yield starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A) accordingto the procedure of Example 2. ¹H NMR (400 MHz, DMSO-d6): δ 2.14 (3H,s), 5.41 (2H, s), 7.11 (1H, t, J=7.8 Hz), 7.18 (1H, m), 7.28 (1H, m),7.63 (1H, m), 7.74 (1H, s), 7.87 (1H, s), 8.32 (1H, s), 8.52 (1H, d,J=7.3 Hz). [M+H] Calc'd for C₁₈H₁₅FN₆, 335; Found, 335.

Example 29:2-[1-[(3-chloro-2-fluorophenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 5% yield starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A) accordingto the procedure of Example 2. ¹H NMR (400 MHz, DMSO-d6): δ 5.41 (2H,s), 7.24-7.33 (2H, m), 7.59 (1H, m), 7.65 (1H, dd, J=5.1 and 1.7 Hz),7.79 (1H, s), 7.91 (1H, s), 8.32 (1H, s), 8.52 (1H, d, J=5.1 Hz). [M+H]Calc'd for C₁₇H₁₂ClFN₆, 355; Found, 355.

Example 30:2-[1-[(2-fluoro-3-methoxyphenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 6% yield starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A) accordingto the procedure of Example 2. ¹H NMR (400 MHz, DMSO-d6): δ 3.84 (3H,s), 5.34 (2H, s), 6.90 (1H, m), 7.15 (2H, 2s), 7.64 (1H, d, J=5.0 Hz),7.74 (1H, s), 7.87 (1H, s), 8.32 (1H, s), 8.53 (1H, d, J=5.2 Hz), 8.63(1H, br s). [M+H] Calc'd for C₁₈H₁₅FN₆O, 351; Found, 351.

Example 31:4-(1H-triazol-4-yl)-2-[1-[2-[2-(trifluoromethyl)phenyl]ethyl]imidazol-4-yl]pyridine

The title compound was prepared in 3% overall yield according to theprocedure of Example 6 starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A). ¹H NMR(400 MHz, DMSO-d6): δ 3.27 (2H, t, J=6.4 Hz), 4.32 (2H, t, J=7.8 Hz),7.46 (2H, m), 7.60-7.81 (6H, m), 8.47-8.63 (2H, m). [M+H] Calc'd forC₁₉H₁₅F₃N₆, 385; Found, 385.

Example 32:2-[1-[2-(2-chlorophenyl)-2-methylpropyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 7% overall yield according to theprocedure of Example 6 starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A). ¹H NMR(400 MHz, DMSO-d6): δ 1.51 (6H, s), 4.61 (2H, s), 7.23-7.37 (5H, m),7.53 (1H, d, J=7.5 Hz), 8.22 (1H, s), 8.42 (1H, s), 8.52 (1H, m). [M+H]Calc'd for C₂₀H₁₉ClN₆, 379; Found, 379.

Example 33:2-[1-(1-phenylpropan-2-yl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine

The title compound was prepared in 1% overall yield according to theprocedure of Example 6 starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A). ¹H NMR(400 MHz, DMSO-d6): δ 0.86 (3H, t, J=7.2 Hz), 2.33 (2H, m), 5.31 (1H,m), 7.33 (1H, d, J=7.3 Hz), 7.38 (1H, t, J=7.2 Hz), 7.46 (1H, s), 7.48(1H, s), 7.73 (1H, dd, J=5.0 and 1.6 Hz), 7.93 (1H, s), 7.98 (1H, s),8.47 (1H, s), 8.54 (1H, d), 8.60 (1H, s). [M+H] Calc'd for C₁₉H₁₈N₆,331; Found, 331.

Example 34:4-(1H-triazol-4-yl)-2-[1-[2-[2-(trifluoromethoxy)phenyl]ethyl]imidazol-4-yl]pyridine

The title compound was prepared in 5% overall yield according to theprocedure of Example 6 starting from2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (Preparation 21A). ¹H NMR(400 MHz, DMSO-d6): δ 3.18 (2H, t, J=7.0 Hz), 4.32 (2H, t, J=7.2 Hz),7.20 (1H, d, J=8.3 Hz), 7.27 (1H, s), 7.62 (1H, dd, J=5.1 and 1.6 Hz),7.64 (1H, d, J=4.5 Hz), 7.83 (1H, d, J=4.5 Hz), 8.28 (1H, s), 8.56 (1H,d, J=5.2 Hz), 8.58 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₉H₁₅F₃N₆O, 401;Found, 401.

Preparation 35A:4-ethynyl-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine

A mixture of2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine-4-carbaldehyde (1.08g, 3.32 mmol) and K₂CO₃ (0.92 g, 6.64 mmol) in MeOH (20 mL) was stirredfor 15 min at rt, then (1-diazo-2-oxo-propyl)-phosphonic acid dimethylester (2.4 eq) was added and stirred for 2 hr at rt. LC/MS showed thereaction was completed, concentrated and purified by flash columnchromatography on silica gel (DCM/MeOH=20/1) to afford the titlecompound (0.8 g, 75%). [M+H] Calc'd for C₂₂H₁₇N₃, 324; Found, 324.

Preparation 35B:4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine

A mixture of 1-(azidomethyl)-4-methoxybenzene (310 mg, 1.86 mmol), KI(617 mg, 3.72 mmol) and Cu(ClO₄)₂.6H₂O (1.376 g, 3.72 mmol) in THF wasstirred for 5 min at rt. Then TEA (375 mg, 3.72 mmol) and4-ethynyl-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine (600 mg,1.86 mmol) were added sequentially and stirred for 1 h at rt. LC/MSshowed the reaction was completed, diluted with EtOAc, washed by 25%NH₃—H₂O, dried, concentrated to give the title compound (1.1 g, 97%).[M+H] Calc'd for C₃₀H₂₅IN₆O, 613; Found, 613.

Preparation 35C:4-[5-fluoro-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine

A mixture of4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine(100 mg, 0.25 mmol) and KF (77 mg, 1.23 mmol) in ACN/H₂O (2 ml/2 ml) wasstirred for 10 min at 160° C. in a microwave oven. LC/MS showed thereaction was completed, H₂O was added, extracted with EtOAc, dried togive the title compound (100 mg, 80%) as a yellow solid. [M+H] Calc'dfor C₃₀H₂₅FN₆O, 505; Found, 505.

Example 35:4-(5-fluoro-1H-triazol-4-yl)-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine

A solution of4-[5-fluoro-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine(100 mg) in TFA (3 mL) was stirred for 5 hr at 65° C. LC/MS showed thereaction was completed. The reaction mixture was concentrated andpurified by prep-HPLC to give the title compound (23 mg, 30%). ¹H NMR(400 MHz, CD₃OD): δ 3.75 (2H, m), 4.95 (2H, m), 7.30-7.58 (4H, m),7.82-7.93 (3H, m), 8.10-8.25 (3H, m), 8.71 (1H, m), 8.73 (1H, m). [M+H]Calc'd for C₂₂H₁₇FN₆, 385; Found, 385.

Preparation 36A:4-[5-chloro-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine

The title compound was prepared in 70% yield according to the procedureof Preparation 35C using KCl. [M+H] Calc'd for C₃₀H₂₅ClN₆O, 521; Found,521.

Example 36:4-(5-chloro-1H-triazol-4-yl)-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine

The title compound was prepared in 10% yield according to the generalprocedure for the preparation of Example 35. ¹H NMR (400 MHz, CD₃OD): δ3.62-3.64 (2H, m), 4.55-4.57 (2H, m), 7.15-7.44 (4H, m), 7.70-8.25 (6H,m), 8.45-8.47 (1H, m), 8.61-8.63 (1H, m). [M+H] Calc'd for C₂₂H₁₇ClN₆,401; Found, 401.

Preparation 37A:4-[1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)triazol-4-yl]-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine

To a mixture of4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine(100 mg, 0.26 mmol), CuI (50 mg, 0.26 mmol), KF (45 mg, 0.78 mmol),Ag₂CO₃ (144 mg, 0.52 mmol) and 1,10-phenanthroline in DMF was addedTMSCF₃ (111 mg, 0.78 mmol) at rt. The reaction mixture was stirred for 2hr at 100° C. in a sealed tube. It was then filtered and separatedbetween water and CH₂Cl₂, dried and concentrated to give the crudecompound (97 mg, 70%). [M+H] Calc'd for C₃₁H₂₅F₃N₆O, 555; Found, 555.

Example 37:2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]-4-[5-(trifluoromethyl)-1H-triazol-4-yl]pyridine

The title compound was prepared in 3% yield according to the generalprocedure for the preparation of Example 35. ¹H NMR (400 MHz, CD₃OD): δ3.65 (2H, t, J=6.8 Hz), 4.59 (2H, t, J=6.8 Hz), 7.18-7.48 (4H, m),7.62-7.64 (1H, m), 7.72 (1H, d, J=8.0 Hz), 7.81 (1H, d, J=8.0 Hz),7.89-8.02 (2H, m), 8.10 (1H, s), 8.58 (1H, s), 8.69 (1H, d, J=4.8 Hz).[M+H] Calc'd for C₂₃H₁₇F₃N₆, 435; Found, 435.

Example 38:4-(5-iodo-1H-triazol-4-yl)-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine

The title compound was prepared in 30% yield according to the generalprocedure for the preparation of Example 35 using4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine.¹H NMR (400 MHz, CD₃OD): δ 3.77 (2H, t, J=6.8 Hz), 4.68 (2H, t, J=6.8Hz), 7.32-7.59 (4H, m), 7.84 (1H, d, J=8.0 Hz), 7.93 (1H, d, J=8.0 Hz),8.11-8.16 (2H, m), 8.20 (1H, s), 8.42 (1H, s), 8.53 (1H, s), 8.75 (1H,d, J=4.2 Hz). [M+H] Calc'd for C₂₂H₁₇IN₆, 493; Found, 493.

Preparation 39A:2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridine-4-carboxylicacid

A mixture of2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine(348 mg, 1 mmol, Preparation 4A) and NaOH (1 mL, 5 mmol) in EtOH (10 mL)was refluxed overnight. LC/MS showed the reaction was completed, cooledto rt and acidified to pH=3-4 by 1N HCl, the solid was filtered anddried to give the title compound (256 mg, 70%). [M+H] Calc'd forC₂₀H₁₈FN₃O₃, 368; Found, 368.

Preparation 39B:[2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]methanol

To a solution of2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridine-4-carboxylicacid (256 mg, 0.7 mmol) in THF was added a solution of LiAlH₄ in THF(0.96 mL, 2.31 mmol, 2.4 M) at 0° C., then stirred for 2 hr at rt. LC/MSshowed the reaction was completed, 0.1 mL H₂O, 0.1 mL NaOH, and 0.3 mLH₂O were added, filtered, concentrated and purified by flash columnchromatography on silica gel (DCM/MeOH=20/1) to give the title compound(123 mg, 50%). [M+H] Calc'd for C₂₀H₂₀FN₃O₂, 354; Found, 354.

Preparation 39C:2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridine-4-carbaldehyde

To a solution of Dess-Martin reagent (221 mg, 0.52 mmol) in THF (10 mL)was added a solution of[2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]methanol(123 mg, 0.35 mmol) at 0° C., then stirred for 2 hr at rt. LC/MS showedthe reaction was completed. NaOH (14.7 mL, 14.7 mmol, 1M) was added toquench the reaction. The reaction mixture was extracted by EtOAc, driedand concentrated to give the crude compound (165 mg, 90%). [M+H] Calc'dfor C₂₀H₁₈FN₃O₂, 352; Found, 352.

Preparation 39D:2-(benzenesulfonyl)-3-[2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]prop-2-enenitrile

A mixture of2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridine-4-carbaldehyde(165 mg, 0.47 mmol), 2-(benzenesulfonyl)acetonitrile (85 mg, 0.47 mmol)and NaHCO₃ (2.35 mL, 0.58 mmol, 0.25 M) in EtOH (10 mL) was stirredovernight at rt. LC/MS showed the reaction was completed, concentratedand purified by prep-TLC (DCM/MeOH=20/1) to give the title compound (170mg, 70%). [M+H] Calc'd for C₂₈H₂₃FN₄O₃S, 515; Found, 515.

Example 39:4-[2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile

A mixture of2-(benzenesulfonyl)-3-[2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]prop-2-enenitrile(170 mg, 0.33 mmol) and NaN₃ (22 mg, 0.33 mmol) in DMF (10 mL) wasstirred for 2 h at 100° C. LC/MS showed the reaction was completed,acidified to pH=3-4 by 1N HCl, and stirred for 30 min, then adjusted topH=7-8 by 1N NaOH, concentrated and purified by HPLC to give the titlecompound (28 mg, 20%). ¹H NMR (300 MHz, DMSO): δ 0.04-0.35 (4H, m),0.92-0.93 (1H, m), 3.55 (3H, s), 3.74-3.92 (2H, m), 6.94-6.95 (1H, m),7.15 (1H, d, J=10.2 Hz), 7.48 (1H, t, J=7.5 Hz), 7.80 (1H, d, J=5.4 Hz),7.87 (1H, s), 8.73 (1H, d, J=5.4 Hz), 8.85 (1H, s). [M+H] Calc'd forC₂₂H₁₈FN₇O, 416; Found, 416.

Preparation 40A:2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-ethynylpyridine

A mixture of2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridine-4-carbaldehyde(1.18 g, 3.32 mmol, Preparation 39C) and K₂CO₃ (0.92 g, 6.64 mmol) inMeOH (20 mL) was stirred for 15 min at rt, then(1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (2.4 eq) was addedand stirred for 2 hr at rt. LC/MS showed the reaction was completed,concentrated and purified by flash column chromatography on silica gel(DCM/MeOH=20/1) to afford the title compound (617 mg, 75%). [M+H] Calc'dfor C₂₁H₁₈FN₃O, 348; Found, 348.

Preparation 40B:2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]pyridine

To a mixture of 1-(azidomethyl)-4-methoxybenzene (415 mg, 2.49 mmol), KI(826 mg, 4.98 mmol) and Cu(ClO₄)₂.6H₂O (1.842 g, 4.98 mmol) in THF whichwas stirred for 5 min at rt, added TEA (503 mg, 4.98 mmol) and2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-ethynylpyridine(617 mg, 2.49 mmol) sequentially. The reaction mixture was stirred for 1h at rt. LC/MS showed the reaction was completed. It was diluted withEtOAc, washed by 25% NH₃—H₂O, dried, and concentrated to give the titlecompound (1.1 g, 70%). [M+H] Calc'd for C₂₉H₂₆FIN₆O₂, 637; Found, 637.

Preparation 40C:4-[5-chloro-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridine

A mixture of2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-[5-iodo-1-[(4-methoxyphenyl)methyl]triazol-4-yl]pyridine(230 mg, 0.35 mmol) and KCl (130 mg, 1.75 mmol) in ACN/H₂O (2 ml/2 ml)was stirred for 10 min at 160° C. in a microwave oven. LC/MS showed thereaction was completed, H₂O was added, extracted with EtOAc, dried togive the title compound (128 mg, 67%) as a yellow solid. [M+H] Calc'dfor C₂₉H₂₆ClFN₆O₂, 545; Found, 545.

Example 40:4-(5-chloro-1H-triazol-4-yl)-2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridine

A solution of4-[5-chloro-1-[(4-methoxyphenyl)methyl]triazol-4-yl]-2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridine(128 mg, 0.235 mmol) in TFA (3 ml) was stirred for 5 h at 65° C. LC/MSshowed the reaction was completed, concentrated, purified by HPLC togive the title compound (7 mg, 7%). ¹H NMR (400 MHz, CD₃OD): δ 0.02-0.34(4H, m), 0.94-0.97 (1H, m), 3.54 (3H, s), 3.77-3.87 (2H, m), 6.88-6.93(1H, m), 7.06 (1H, d, J=12.8 Hz), 7.44 (1H, t, J=8.0 Hz), 7.78 (1H, s),7.91 (1H, d, J=4.2 Hz), 8.69 (1H, d, J=4.2 Hz), 8.94 (1H, s). [M+H]Calc'd for C₂₁H₁₈ClFN₆O, 425; Found, 425.

Preparation 41A:2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-[5-fluoro-1-[(4-methoxyphenyl)methyl]triazol-4-yl]pyridine

The title compound was prepared in 70% yield according to the procedureof Preparation 35C. [M+H] Calc'd for C₂₉H₂₆F₂N₆O₂, 529; Found, 529.

Example 41:2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]-4-(5-fluoro-1H-triazol-4-yl)pyridine

The title compound was prepared in 10% yield according to the generalprocedure for the preparation of Example 35. ¹H NMR (400 MHz, CD₃OD): δ0.04-0.28 (4H, m), 0.83-0.87 (1H, m), 3.43-3.80 (5H, m), 6.81-7.01 (2H,m), 7.34-7.68 (3H, m), 7.98-8.98 (2H, m). [M+H] Calc'd for C₂₁H₁₈F₂N₆O,409; Found, 409.

Example 42:1-(cyclopropylmethyl)-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

To a solution of 6-chloro-3,4-pyridinediamine (12.5 g, 87 mmol) in HCl(Conc, 100 mL) was added NaNO₂ (6.6 g, 96 mmol) in water (20 mL)dropwise at 0° C. for 1 h. Upon completion, the pH was adjusted to 10with Na₂CO₃ solution. The slurry was filtered, the solid was washed withPE and dried in vacuo to afford6-chloro-1H-[1,2,3]triazolo[4,5-c]pyridine (10.0 g, 75%) as a yellowsolid. [M+H] Calc'd for C₅H₃ClN₄, 155; Found, 155.

To a mixture of 6-chloro-1H-[1,2,3]triazolo[4,5-c]pyridine (4.62 g, 30mmol), DIEA (7.8 g, 60 mmol), in DMF (50 mL) was added SEMCl (6.0 g, 36mmol) at 0° C. and the reaction was stirred at ambient temperature for16 hours. The mixture was concentrated in vacuo and purified bychromatography (ethyl acetate) to afford6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridine(5.1 g, 61%) as a yellow solid. [M+H] Calc'd for C₁₁H₁₇ClN₄OSi, 285;Found, 285.

To a solution of compound6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridine(6.2 g, 2.2 mmol) in MeOH (200 mL), was added DPPP (943 mg, 2.2 mmol),Et₃N (4.4 g, 44 mmol), and Pd(OAc)₂ (490 mg, 2.2 mmol) at roomtemperature. The mixture was heated at 100° C. for 48 h under 5 MPacarbon monoxide. The reaction was filtered, and the filtrateconcentrated in vacuo. The residue was purified by column chromatography(EA/PE=1/1) to afford methyl1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridine-6-carboxylate(2.8 g, 41%) as a yellow solid. [M+H] Calc'd for C₁₃H₂₀N₄O₃Si, 309;Found, 309.

To a solution of methyl1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridine-6-carboxylate(2.8 g, 9 mmol) in MeOH (30 mL) was added NaBH₄ (1.4 g, 36 mmol) at 0°C. The mixture was stirred at ambient temperature overnight. Uponcompletion, the reaction was concentrated in vacuo and purified bychromatograph (EA/PE=2/1) to afford(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)methanol(2.4 g, 95%) as a yellow oil. [M+H] Calc'd for Cl₂H₂₀N₄O₂Si, 281; Found,281.

To a solution of(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)methanol(2.4 g, 8.6 mmol) in DCM (100 mL) was added MnO₂ (4.6 g, 36 mmol) at 0°C. The mixture was stirred at ambient temperature overnight. Uponcompletion, the reaction was concentrated in vacuo and the residuepurified by column chromatography (EA/PE=1/1) to afford1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridine-6-carbaldehyde(1.0 g, 40%) as a yellow oil. [M+H] Calc'd for Cl₂H₁₈N₄O₂Si, 279; Found,279.

To a solution of1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridine-6-carbaldehyde(0.9 g, 3.2 mmol) and TosMic (0.6 g, 3.2 mmol) in EtOH (50 mL) was addedKCN (30 mg, 3.2 mmol) at ambient temperature. The reaction was allowedto stir for 20 min. Upon completion, the mixture was concentrated invacuo and a solution of NH₃ in MeOH (1 g/20 mL) was added. The reactionwas stirred for 16 h at 125° C. The reaction was concentrated in vacuoand the residue purified by column chromatography (EA=100) to give4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole(350 mg, 34.5%). [M+H] Calc'd for C₁₄H₂₀N₆OSi, 317; Found, 317.

A mixture of4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole(100 mg, 0.3 mmol), 1-(bromomethyl)cyclopropane (81 mg, 0.6 mmol) andK₂CO₃ (85 mg, 0.6 mmol) in DMF (10 mL) was allowed to stir overnight at70° C. The reaction mixture was filtered and the filtrate concentratedin vacuo. The residue was purified by column chromatography (EA/PE=1/1)to give1-(cyclopropylmethyl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazoleas a yellow solid in good yield (80 mg, 72%): [M+H] Calc'd forC₁₈H₂₆N₆OSi, 371; Found, 371.

To a vial charged with1-(cyclopropylmethyl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole(60 mg, 0.16 mmol) in DCM (5 mL) was added TFA (1 mL) and allowed tostir at ambient temperature for 2 h. The reaction mixture wasconcentrated in vacuo and the residue purified by prep-HPLC to afford1-(cyclopropylmethyl)-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole(17 mg, 44%): ¹H NMR (400 MHz, CD₃OD): δ 0.59-0.61 (2H, m), 0.81-0.83(2H, m), 1.47-1.49 (1H, m), 4.20 (2H, d, J=7.6 Hz), 8.36-8.39 (2H, m),9.06 (1H, s), 9.49 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.694 min. [M+H]Calc'd for C₁₂H₁₂N₆, 241; Found, 241.

Example 43:4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1-(2,2,2-trifluoroethyl)-1H-imidazole

The title compound was prepared in 50% yield according to the procedurefor example 42. ¹H NMR (400 MHz, CD₃OD): δ 5.15-5.17 (2H, m), 8.20 (1H,s), 8.36 (1H, s), 8.51 (1H, s), 9.49 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.639 min. [M+H]Calc'd for C₁₀H₇F₃N₆, 267; Found, 267.

Example 44:1-benzyl-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 44% yield according to the procedurefor example 42. ¹H NMR (400 MHz, CD₃OD): δ 5.47 (2H, s), 7.43-7.49 (5H,m), 8.16 (1H, s), 8.28 (1H, s), 8.79 (1H, s), 9.43 (1H, s). LCMS (mobilephase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.439min. [M+H] Calc'd for C₁₅H₁₂N₆, 277; Found, 277.

Example 45:1-[(2-chlorophenyl)methyl]-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 43% yield according to the procedurefor example 42. ¹H NMR (400 MHz, DMSO-d₆): δ 5.46 (2H, s), 7.37-7.45(3H, m), 7.51-7.56 (1H, m), 8.06 (1H, s), 8.26 (1H, s), 8.55 (1H, s),9.44 (1H, s). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=2.718 min. [M+H] Calc'd for C₁₅H₁₁ClN₆, 311;Found, 311.

Example 46:1-[(3-chlorophenyl)methyl]-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 52% yield according to the procedurefor example 42. ¹H NMR (400 MHz, DMSO-d₆): δ 5.49 (2H, s), 7.42-7.46(3H, m), 7.54 (1H, s), 8.21 (1H, s), 8.30 (1H, s), 8.87 (1H, s), 9.44(1H, s). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac):purity is >95%, Rt=2.815 min. [M+H] Calc'd for C₁₅H₁₁ClN₆, 311; Found,311.

Example 47:1-[(4-chlorophenyl)methyl]-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 48% yield according to the procedurefor example 42. ¹H NMR (400 MHz, DMSO-d₆): δ 5.39 (2H, s), 7.46-7.51(4H, m), 8.19 (1H, s), 8.27 (1H, s), 8.71 (1H, s), 9.47 (1H, s). LCMS(mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=2.682 min. [M+H] Calc'd for C₁₅H₁₁ClN₆, 311; Found, 311.

Example 48:1-[(3,4-dichlorophenyl)methyl]-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 48% yield according to the procedurefor example 42. ¹H NMR (400 MHz, DMSO-d₆): δ 5.53 (2H, s), 7.45 (1H,J=8.0 Hz, d), 7.65 (1H, J=8.0 Hz, d), 7.74 (1H, s), 8.31 (1H, s), 8.33(1H, s), 9.11 (1H, s), 9.47 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.682 min. [M+H]Calc'd for C₁₅H₁₀Cl₂N₆, 346; Found, 346.

Example 49:1-(4-chlorophenyl)-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

A mixture of compound4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole(100 mg, 0.3 mmol), 4-chlorophenylboronic acid (56 mg, 0.6 mmol),Cu(OAc)₂ (82 mg), pyridine (0.2 mL) in DCM (10 mL) was allow to stirovernight at ambient temperature. Upon completion, the reaction wasfiltered and concentrated in vacuo and the residue purified by columnchromatography (EA/PE=1/1) to give crude4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole.To a mixture of the crude intermediate in DCM (5 mL) was added TFA (1mL) and stirred at room temperature for 2 hours. The mixture wasconcentrated in vacuo and purified by prep-HPLC to afford title compound(4 mg, 10%). ¹H NMR (300 MHz, DMSO-d₆): δ 7.60-7.63 (2H, d, J=9.0 Hz),7.84-7.87 (2H, d, J=9.0 Hz), 8.19 (1H, s), 8.38 (1H, s), 8.46 (1H, s),9.43 (1H, s). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=2.972 min. [M+H] Calc'd for C₁₄H₉ClN₆, 297;Found, 297.

Example 50:1-(2-chlorophenyl)-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 6% yield according to the procedurefor example 49. ¹H NMR (300 MHz, CD₃OD): δ 7.61-7.69 (2H, m), 7.74-7.79(2H, m), 8.49 (1H, s), 8.53 (1H, s), 9.15 (1H, s), 9.58 (1H, s). LCMS(mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=2.982 min. [M+H] Calc'd for C₁₄H₉ClN₆, 297; Found, 297.

Example 51:1-(3-chlorophenyl)-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 8% yield according to the procedurefor example 49. ¹H NMR (300 MHz, DMSO-d₆): δ 7.45-7.61 (2H, m),7.79-7.84 (1H, m), 8.04 (1H, s), 8.20-8.23 (1H, m), 8.48-8.51 (1H, m),8.59-861 (1H, m), 9.45-9.46 (1H, s).

LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02% NH4Ac): purityis >95%, Rt=3.105 min. [M+H] Calc'd for C₁₄H₉ClN₆, 297; Found, 297.

Example 52:1-(3,5-dichlorophenyl)-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 6% yield according to the procedurefor example 49. ¹H NMR (400 MHz, DMSO-d₆): δ 7.63 (1H, s), 8.05 (2H, s),8.19 (1H, s), 8.52-8.59 (2H, m), 9.45 (1H, br). LCMS (mobile phase:5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.682 min.[M+H] Calc'd for C₁₄H₈Cl₂N₆, 331; Found, 331.

Example 53:5-(4-fluorophenyl)-1-methyl-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

A mixture of6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridine(1.4 g, 5.0 mmol), 1-methyl-4-(tributylstannyl)-1H-imidazole (2.5 g, 5.0mmol), and Pd(PPh₃)₄ (530 mg, 0.5 mmol) in DMF (20 mL) was heated at130° C. for 5 h. Upon completion, the reaction mixture was concentratedin vacuo and the residue purified by column chromatography(DCM/MeOH=10/1) to give1-methyl-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole(1.5 g, 90% yield).

A round-bottom flask charged with1-methyl-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole(660 mg, 2.0 mmol), and NBS (356 mg, 2.1 mmol) in DCM (10 mL) was allowto stir for 2 h at ambient temperature. Upon completion, water was addedand the aqueous layer extracted by DCM. The combined organic layers weresuccessively washed with brine, dried over Na₂SO₄ and concentrated invacuo. The resulting crude5-bromo-1-methyl-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole(700 mg) was used in the next step without further purification.

A mixture of5-bromo-1-methyl-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-1H-imidazole(0.5 mmol), 4-fluorophenylboronic acid (140 mg, 1.0 mmol), Pd(dppf)Cl₂(37 mg, 0.05 mmol) and 2M Na₂CO₃ (1.0 mmol, 2.0 eq) in 5 mL dioxane waskept at 130° C. overnight. Upon completion, the reaction mixture wasconcentrated in vacuo and the residue was purified by columnchromatography (DCM/MeOH=50/1) to afford the title compound (50 mg,30%). ¹H NMR (300 MHz, DMSO-d₆): δ 9.17 (1H, s), 7.90 (1H, s), 7.80 (1H,s), 7.44-7.48 (2H, m), 7.25 (t, J=8.7 Hz, 2H), 3.61 (3H, s). LCMS(mobile phase: 5%-95% Acetonitrile-Water-0.1% TFA) purity is >95%,Rt=2.427 min. [M+H] Calc'd for C₁₅H₁₁FN₆, 295; Found, 295.

Example 54:5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methyl-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole

The title compound was prepared in 28% yield according to the procedurefor example 53. ¹H NMR (300 MHz, CD₃OD): δ 9.47 (1H, s), 9.18 (1H, s),7.52-7.57 (1H, m), 7.49 (1H, s), 7.14-7.18 (1H, m), 6.96-7.02 (1H, m),3.89-3.94 (m, 2H), 3.82 (s, 3H), 1.02-1.07 (m, 1H), 0.06-0.43 (m, 4H).LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.1% NH₄Ac): purityis >95%, Rt=2.855 min. [M+H] Calc'd for C₁₉H₁₇FN₆O, 365; Found, 365.

Preparation 55A:2-(5-bromo-1-(2-chlorobenzyl)-1H-imidazol-4-yl)isonicotinonitrile

The title compound was prepared according to the procedure ofPreparation 3A starting from2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbonitrile.[M+H] Calc'd for C₁₆H₁₀BrClN₄, 373; Found, 373.

Example 55:2-(5-bromo-1-(2-chlorobenzyl)-1H-imidazol-4-yl)-4-(2H-1,2,3-triazol-4-yl)pyridine

The title compound was prepared in 12% yield according to the procedureof Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 5.43 (2H, s), 6.75 (1H, dd,J=7.0 and 2.0 Hz), 7.34-7.40 (2H, m), 7.55 (1H, dd, J=7.8 and 1.8 Hz),7.73 (1H, dd, J=5.1 and 1.6 Hz), 8.16 (1H, s), 8.46 (1H, s), 8.63-8.68(2H, m). [M+H] Calc'd for C₁₇H₂BrClN₆, 417; Found, 417.

Example 56:2-[1-[(2,3-Dichlorophenyl)methyl]imidazol-4-yl]-4-(5-trifluoromethyl-1H-triazol-4-yl)pyridine

The title compound was prepared in 1% yield according to the procedureof Example 37. ¹H NMR (400 MHz, CD₃OD): δ 5.60 (2H, s), 7.39-7.41 (2H,m), 7.61-7.68 (2H, m), 8.16-8.28 (2H, m), 8.72-8.77 (2H, m). [M+H]Calc'd for C₁₈H₁₁Cl₂F₃N₆, 439; Found, 439.

II. Biological Evaluation Example 1: In Vitro Enzyme Inhibition Assay

This assay determines the ability of a test compound to inhibit FBXL11,FBXL10, and PHF8 demethylase activity. Baculovirus expressed FBXL11(GenBank Accession #NM 012308, AA1-1162) was purchased from BPSBioscience (Cat#50102). Baculovirus expressed FBXL10 (GenBank Accession#NM 032590, AA 1-650) was purchased from BPS Bioscience (Cat #50120).Baculovirus expressed PHF8 (GenBank Accession NP_055922.1) was purchasedfrom Active Motif (Cat#31435).

FBXL11 Assay

The ability of test compounds to inhibit the activity of FBXL11 wasdetermined in 384-well plate format under the following reactionconditions: 0.15 nM FBXL11, 30 nM H3K36me2-biotin labeled peptide(Anaspec cat #64442), 0.2 μM alpha-ketoglutaric acid in assay buffer of50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μMsodium L-ascorbate, 5 μM ammonium iron(II) sulfate. Reaction product isdetermined quantitatively by AlphaScreen detection after the addition ofdetection reagents anti-H3K36me1 antibody, AlphaScreen®Streptavidin-coated Donor beads, and AlphaScreen® Protein A Acceptorbeads in 50 mM HEPES, pH7.3, 10 mM NaCl, 0.005% Brij35, 5 mM EDTA, 2mg/ml BSA to final 10 μg/ml beads.

The assay reaction was initiated by the following: 3 μl of the mixtureof 90 nM H3K36me2-biotin labeled peptide and 0.6 μM alpha-ketoglutaricacid with 3 μl of 11-point serial diluted inhibitor in 3% DMSO are addedto each well of 384 well Proxiplate (Perkin Elmer), followed by theaddition of 3 μl of 0.45 nM FBXL11 to initiate the reaction. Thereaction mixture is incubated at room temperature for 1 hour, andterminated by the addition of 3 μl of appropriate dilution of antiH3K36me1 antibody in 50 mM HEPES, pH7.3, 10 mM NaCl, 0.005% Brij35, 5 mMEDTA, 2 mg/ml BSA. Plates will then incubated at room temperature for 40minutes, followed by addition of 3 ul of 50 μg/ml AlphaScreen®Streptavidin-coated Donor beads and AlphaScreen® Protein A Acceptorbeads in 50 mM HEPES, pH7.3, 10 mM NaCl, 0.005% Brij35, 5 mM EDTA, 2mg/ml BSA. Plates will then be read by EnVision Multilabel Reader inAlphaScreen mode after minimum 2 hour incubation at room temperature.The AlphaScreen signal for each well is used to determine inhibitionconstant (IC₅₀).

FBXL10 Assay

The ability of test compounds to inhibit the activity of FBXL10 wasdetermined in 384-well plate format under the following reactionconditions: 0.3 nM FBXL10, 30 nM H3K36me2-biotin labeled peptide(Anaspec cat #64442), 0.2 μM alpha-ketoglutaric acid in assay buffer of50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μMsodium L-ascorbate, 5 μM ammonium iron(II) sulfate. Reaction product isdetermined quantitatively by AlphaScreen detection after the addition ofdetection reagents anti-H3K36me1 antibody, AlphaScreen®Streptavidin-coated Donor beads, and AlphaScreen® Protein A Acceptorbeads in 50 mM HEPES, pH7.3, 10 mM NaCl, 0.005% Brij35, 5 mM EDTA, 2mg/ml BSA to final 10 μg/ml beads.

The assay reaction was initiated by the following: 3 μl of the mixtureof 90 nM H3K36me2-biotin labeled peptide and 0.6 μM alpha-ketoglutaricacid with 3 μl of 11-point serial diluted inhibitor in 3% DMSO are addedto each well of 384 well Proxiplate (Perkin Elmer), followed by theaddition of 3 μl of 0.9 nM FBXL10 to initiate the reaction. The reactionmixture is incubated at room temperature for 1 hour, and terminated bythe addition of 3 μl of appropriate dilution of anti H3K36me1 antibodyin 50 mM HEPES, pH7.3, 10 mM NaCl, 0.005% Brij35, 5 mM EDTA, 2 mg/mlBSA. Plates will then incubated at room temperature for 40 minutes,followed by addition of 3 ul of 50 μg/ml AlphaScreen®Streptavidin-coated Donor beads and AlphaScreen® Protein A Acceptorbeads in 50 mM HEPES, pH7.3, 10 mM NaCl, 0.005% Brij35, 5 mM EDTA, 2mg/ml BSA. Plates will then be read by EnVision Multilabel Reader inAlphaScreen mode after minimum 2 hour incubation at room temperature.The AlphaScreen signal for each well is used to determine inhibitionconstant (IC₅₀).

PHF8 Assay

The ability of test compounds to inhibit the activity of PHF8 wasdetermined in 384-well plate format under the following reactionconditions: 3 nM PHF8, 200 nM H3K9me1-biotin labeled peptide (Anaspeccat #64358), 0.5 μM alpha-ketoglutaric acid in assay buffer of 50 mMHEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 5 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-unmodified-histone H3 lysine 9/lysine27 (H3K9/K27)antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detectionbuffer (PerkinElmer) at a final concentration of 25 nM and 0.5 nM,respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 600 nM H3K9me1-biotin labeled peptide and 1.5 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO wereadded to each well of the plate, followed by the addition of 2 μl of 9nM PHF8 to initiate the reaction. The reaction mixture was incubated atroom temperature for 15 minutes, and terminated by the addition of 6 μlof 5 mM EDTA in LANCE detection buffer containing 50 nM PhycolinkStreptavidin-allophycocyanin and 1 nM Europium-anti-unmodified H3K9/K27antibody. Plates were read by EnVision Multilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hourincubation at room temperature. A ratio was calculated (665/615) foreach well and fitted to determine inhibition constant (IC₅₀).

The ability of the compounds disclosed herein to inhibit demethylaseactivity was quantified and the respective IC₅₀ value was determined.Table 3 provides the IC₅₀ values of various compounds disclosed herein.

TABLE 3 Chemical FBXL11 PHF8 Synthesis FBXL10 IC₅₀ IC₅₀ Example NameIC₅₀ (μM) (μM) (μM) 1 2-(1-methylimidazol-4-yl)-4-(1H-triazol-4- B Byl)pyridine 2 2-[1-[(2-chlorophenyl)methyl]imidazol-4- A B Byl]-4-(1H-triazol-4-yl)pyridine 32-[5-(4-fluorophenyl)-1-methylimidazol-4- A Byl]-4-(1H-triazol-4-yl)pyridine 4 2-[5-[2-(cyclopropylmethoxy)-4- A A Cfluorophenyl]-1-methylimidazol-4-yl]-4- (1H-triazol-4-yl)pyridine 52-[1-(1-phenylethyl)imidazol-4-yl]-4-(1H- A A B triazol-4-yl)pyridine 62-[1-[2-(2-chlorophenyl)ethyl]imidazol-4- A A Ayl]-4-(1H-triazol-4-yl)pyridine 72-[1-[2-(2-methoxyphenyl)ethyl]imidazol- A A B4-yl]-4-(1H-triazol-4-yl)pyridine 82-[1-(1,2,3,4-tetrahydronaphthalen-1- A A Bylmethyl)imidazol-4-yl]-4-(1H-triazol-4- yl)pyridine 92-[1-[2-(2-ethoxyphenyl)ethyl]imidazol-4- A A Byl]-4-(1H-triazol-4-yl)pyridine 104-(1H-triazol-4-yl)-2-[1-[2-[2-(2,2,2- A Btrifluoroethoxy)phenyl]ethyl]imidazol-4- yl]pyridine 11 2-[1-[2-[2- A B(cyclopropylmethoxy)phenyl]ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 12 2-[1-(3,4-dihydro-2H-chromen-4- A Aylmethyl)imidazol-4-yl]-4-(1H-triazol-4- yl)pyridine 134-[2-[1-[(2-chlorophenyl)methyl]imidazol- A C4-yl]pyridin-4-yl]-1H-triazole-5- carbonitrile 14 4-[2-[1-[(2,3- A Cdichlorophenyl)methyl]imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile 154-[2-[1-(1,2,3,4-tetrahydronaphthalen-1- A Bylmethyl)imidazol-4-yl]pyridin-4-yl]-1H- triazole-5-carbonitrile 164-[2-[1-(2-naphthalen-1-ylethyl)imidazol- A B4-yl]pyridin-4-yl]-1H-triazole-5- carbonitrile 17 2-[1-[2-(2- A Cphenylmethoxyphenyl)ethyl]imidazol-4- yl]-4-(1H-triazol-4-yl)pyridine 182-[1-[2-(2-phenoxyphenyl)ethyl]imidazol- A C4-yl]-4-(1H-triazol-4-yl)pyridine 19 2-[1-[(2,3- A Bdichlorophenyl)methyl]imidazol-4-yl]-4- (5-iodo-1H-triazol-4-yl)pyridine20 2-[1-[(2,3- A B dichlorophenyl)methyl]imidazol-4-yl]-4-(5-fluoro-1H-triazol-4-yl)pyridine 21 2-[1-[(2,3- A A Bdichlorophenyl)methyl]imidazol-4-yl]-4- (1H-triazol-4-yl)pyridine 222-[1-[[2-chloro-3- A A B (trifluoromethyl)phenyl]methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 232-[1-(2-naphthalen-1-ylethyl)imidazol-4- A A Byl]-4-(1H-triazol-4-yl)pyridine 24 2-[5-(4-fluoro-3-methoxyphenyl)-1- AB methylimidazol-4-yl]-4-(1H-triazol-4- yl)pyridine 252-[5-(3-ethoxy-4-fluorophenyl)-1- A B Cmethylimidazol-4-yl]-4-(1H-triazol-4- yl)pyridine 26 2-[1-[[2-fluoro-3-B C (trifluoromethoxy)phenyl]methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 272-[1-[2-(2-phenylphenyl)ethyl]imidazol-4- B Cyl]-4-(1H-triazol-4-yl)pyridine 28 2-[1-[(2-fluoro-3- A Bmethylphenyl)methyl]imidazol-4-yl]-4- (1H-triazol-4-yl)pyridin 292-[1-[(3-chloro-2- A A fluorophenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 30 2-[1-[(2-fluoro-3- A Bmethoxyphenyl)methyl]imidazol-4-yl]-4- (1H-triazol-4-yl)pyridine 314-(1H-triazol-4-yl)-2-[1-[2-[2- A B(trifluoromethyl)phenyl]ethyl]imidazol-4- yl]pyridine 322-[1-[2-(2-chlorophenyl)-2- A B methylpropyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine 33 2-[1-(1-phenylpropan-2-yl)imidazol-4-yl]- B C4-(1H-triazol-4-yl)pyridine 34 4-(1H-triazol-4-yl)-2-[1-[2-[2- A B(trifluoromethoxy)phenyl]ethyl]imidazol- 4-yl]pyridine 354-(5-fluoro-1H-triazol-4-yl)-2-[1-(2- A Bnaphthalen-1-ylethyl)imidazol-4- yl]pyridine 364-(5-chloro-1H-triazol-4-yl)-2-[1-(2- A Cnaphthalen-1-ylethyl)imidazol-4- yl]pyridine 372-[1-(2-naphthalen-1-ylethyl)imidazol-4- A Dyl]-4-[5-(trifluoromethyl)-1H-triazol-4- yl]pyridine 384-(5-iodo-1H-triazol-4-yl)-2-[1-(2- A D naphthalen-1-ylethyl)imidazol-4-yl]pyridine 39 4-[2-[5-[2-(cyclopropylmethoxy)-4- A Cfluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile 404-(5-chloro-1H-triazol-4-yl)-2-[5-[2- A D(cyclopropylmethoxy)-4-fluorophenyl]-1- methylimidazol-4-yl]pyridine 412-[5-[2-(cyclopropylmethoxy)-4- A Cfluorophenyl]-1-methylimidazol-4-yl]-4-(5-fluoro-1H-triazol-4-yl)pyridine 42 1-(cyclopropylmethyl)-4-{1H- A C[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 434-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}- B C1-(2,2,2-trifluoroethyl)-1H-imidazole 441-benzyl-4-{1H-[1,2,3]triazolo[4,5- A A B c]pyridin-6-yl}-1H-imidazole45 1-[(2-chlorophenyl)methyl]-4-{1H- A A C[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 461-[(3-chlorophenyl)methyl]-4-{1H- A A C[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 471-[(4-chlorophenyl)methyl]-4-{1H- A A C[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 481-[(3,4-dichlorophenyl)methyl]-4-{1H- A A C[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 491-(4-chlorophenyl)-4-{1H- A A C [1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole 50 1-(2-chlorophenyl)-4-{1H- A A C[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 511-(3-chlorophenyl)-4-{1H- B B C [1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole 52 1-(3,5-dichlorophenyl)-4-{1H- B C[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 535-(4-fluorophenyl)-1-methyl-4-{1H- B C[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 545-[2-(cyclopropylmethoxy)-4- B C fluorophenyl]-1-methyl-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H- imidazole 552-(5-bromo-1-(2-chlorobenzyl)-1H- A Bimidazol-4-yl)-4-(2H-1,2,3-triazol-4- yl)pyridine Note: Biochemicalassay IC₅₀ data are designated within the following ranges: A: ≦0.10 μMB: >0.10 μM to ≦1.0 μM C: >1.0 μM to ≦10 μM D: >10 μM

Example 2: In Vitro Cell-Based Assay Mia Paca-2 Pancreatic Cell LineExpression Assay for KDM2B-Related Genes

Gene expression assay to assess the ability of KDM2B small moleculeinhibitors to activate the expression of KDM2B-bound genes of theestablished Mia Paca-2 cancer cell line.

Assay Background

The KDM2B protein has been shown to regulate the proliferation of AML,pancreatic and breast cancer. To demonstrate the specificity of smallmolecules for KDM2B's enzymatic activity, an assay to measure the reliefof suppression caused by KDM2B in the established pancreatic cancer cellline model Mia Paca-2 was employed.

Assay Principle

This gene expression assay is a real-time PCR assay which quantifies theamount of messenger RNA from genes that are normally repressed by KDM2Binteracting with EZH2 compared with a control GAPDH gene whoseexpression is not regulated by KDM2B. The amount of gene expression iscorrelated to the amount of small molecule inhibition of KDM2B'senzymatic activity.

Assay Method

The established cancer cell line Mia Paca-2 was purchased from AmericanType Culture Collection (ATCC) and routinely passaged according to ATCCpublished protocols. Cells were seeded at a density of 40,000 per96-well. 24 hours after plating, cells received final concentrations of20 nM, 40 nM, 80 nM and 320 nM of test compound. Time-matched controlwells of 0.1% DMSO treatment were also included. Cells were incubatedwith test compound for 3, 6, 24 and 48 hrs at 37° C., 5% CO₂. At the endof each of the compound incubation period, media was removed and cellswere trypsinized according to the ATCC published protocol. mRNA was thenharvested from the cell samples using a RNeasy kit (Qiagen). mRNA wasquantified and qualified using a Nanodrop machine (Thermo Scientific).mRNA was converted to cDNA using the High-Capacity cDNA ReverseTranscription Kit (Applied Biosystems). Equal amounts of cDNA weresubjected to real-time PCR using Taqman Universal Master Mix (ThermoScientific). The following Taqman gene expression assays were used fordetection on a Viaa7 Real-time PCR system: Hs00224960_m1, Hs00164982_m1,Hs00907496_m1 and Hs02758991_g1 (Thermo Scientific). Data was analyzedusing the delta-delta Ct method to calculate fold enrichment over DMSOsample gene expression.

Table 4 provides the cellular IC₅₀ values of various substitutedheterocyclic compounds disclosed herein.

TABLE 4 Chemical Cellular Synthesis IC₅₀ Example Name (μM) 372-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]-4-[5- B(trifluoromethyl)-1H-triazol-4-yl]pyridine 412-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1- Cmethylimidazol-4-yl]-4-(5-fluoro-1H-triazol-4- yl)pyridine Note:Cellular assay IC₅₀ data are designated within the following ranges: A:≦0.10 μM B: >0.10 μM to ≦1.0 μM C: >1.0 μM to ≦10 μM D: >10 μM

III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Tablet

A tablet is prepared by mixing 48% by weight of a compound of Formula(I) or (III), or a pharmaceutically acceptable salt thereof, 45% byweight of microcrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

We claim:
 1. A compound having the structure of Formula (Ic),

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen,halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, orheteroarylalkyl; R² is alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, orheteroarylalkyl; R³ is hydrogen; R⁴ is hydrogen, C₁-C₄alkyl,C₁-C₄alkene, C₁-C₄alkyne, halogen, or —CN; and each R⁵ is independentlyhydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is alkyl.
 3. The compound of any one of claims 1-2, or apharmaceutically acceptable salt thereof, wherein R² is methyl.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is carbocyclyl or carbocyclylalkyl.
 5. The compound of claim4, or a pharmaceutically acceptable salt thereof, wherein R² is—(C₁-C₆alkylene)carbocyclyl.
 6. The compound of claim 4 or 5, or apharmaceutically acceptable salt thereof, wherein carbocyclyl is1,2,3,4-tetrahydronaphthyl optionally substituted with one or moregroups selected from halogen, hydroxy, —CN, alkyl, alkoxy, alkylamino,aryl, carbocyclyl, heterocyclyl, carbocyclylalkyl, andheterocyclylalkyl.
 7. The compound of claim 6, or a pharmaceuticallyacceptable salt thereof, wherein the (C₁-C₆alkylene) is a C₁alkylene, ora C₂alkylene.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is heterocyclyl orheterocyclylalkyl.
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is heteroaryl or heteroarylalkyl.10. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R² is aryl or aralkyl.
 11. The compound of claim 10, ora pharmaceutically acceptable salt thereof, wherein the aralkyl is—(C₁-C₆alkylene)aryl.
 12. The compound of claim 10 or 11, or apharmaceutically acceptable salt thereof, wherein the aryl is a phenyloptionally substituted with one or more groups selected from halogen,hydroxy, —CN, alkyl, alkoxy, alkylamino, aryl, carbocyclyl,heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl.
 13. The compoundof claim 12, or a pharmaceutically acceptable salt thereof, wherein(C₁-C₆alkylene) is C₁alkylene, or a C₂alkylene.
 14. The compound ofclaim 10 or 11, or a pharmaceutically acceptable salt thereof, whereinaryl is naphthyl optionally substituted with one or more groups selectedfrom halogen, hydroxy, —CN, alkyl, alkoxy, alkylamino, aryl,carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl. 15.The compound of claim 14, or a pharmaceutically acceptable salt thereof,wherein (C₁-C₆alkylene) is C₁alkylene, or a C₂alkylene.
 16. The compoundof any one of claims 1-15, or a pharmaceutically acceptable saltthereof, wherein R¹ is hydrogen or aryl.
 17. The compound of claim 16,or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen.18. The compound of claim 16, or a pharmaceutically acceptable saltthereof, wherein R¹ is aryl.
 19. The compound of claim 18, or apharmaceutically acceptable salt thereof, wherein the aryl is a phenyloptionally substituted with one or more groups selected from halogen,hydroxy, —CN, alkyl, alkoxy, —O-(cycloalkylalkyl), alkylamino, aryl,carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl. 20.The compound of claim 19, or a pharmaceutically acceptable salt thereof,wherein the phenyl is substituted with one or more groups selected fromhalogen, alkoxy, or —O-(cycloalkylalkyl).
 21. The compound of any one ofclaims 1-20, or a pharmaceutically acceptable salt thereof, wherein R⁴is hydrogen.
 22. The compound of any one of claims 1-20, or apharmaceutically acceptable salt thereof, wherein R⁴ is —CN.
 23. Thecompound of any one of claims 1-20, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁-C₄alkene, or C₁-C₄alkyne.
 24. Thecompound of any one of claims 1-20, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen.
 25. The compound of any one ofclaims 1-20, or a pharmaceutically acceptable salt thereof, wherein R⁴is C₁-C₄alkyl.
 26. The compound of claim 25, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₁-C₄alkyl, and the alkyl issubstituted with at least one fluoro.
 27. The compound of claim 26, or apharmaceutically acceptable salt thereof, wherein R⁴ is CH₂F, CHF₂, orCF₃.
 28. The compound of claim 27, or a pharmaceutically acceptable saltthereof, wherein R⁴ is CF₃.
 29. A pharmaceutical composition comprisinga compound of any of the preceeding claims, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.
 30. A method for inhibiting histone demethylase enzymecomprising contacting the histone demethylase enzyme with a compound ofany of the preceeding claims.
 31. A method for treating cancer in asubject in need thereof comprising administering to the subject acomposition comprising a compound of any of the preceeding claims, or apharmaceutically acceptable salt thereof.